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How is the urea cycle regulated with respect to protein deficit?

How is the urea cycle regulated with respect to protein deficit?



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Proteins cannot be stored in the body. Excess proteins from the diet are deaminated in the urea cycle that takes place in the liver. The liver is the first contact since these amino acids are delivered through the portal circulation.

What I do not understand is what controls the extent of amino acid breakdown in the liver. For example, suppose there is a man who hasn't had protein in a month, and has a net protein deficit, what determines that there shouldn't be much deamination in the liver?

For carbohydrates and sugars, insulin and glucagon balance regulate the main enzymes controlling the steps in glucose phosphorylation hence maintaining homeostasis. Since this is at an organismal level and not the cellular level, like glucose, I would expect the control of urea cycle also to be hormonal. Since there is no hormone that reflects protein status (at least to my knowledge), what determines the activity of the urea cycle?


Preamble

This question is extremely broad because, rather than there being a 'one-click' answer, whole areas of amino acid metabolism need to be considered. This is both inappropriate and impossible to do here - even if I understood everthing about it (which I certainly don't). However I shall provide a specific biochemical answer (or partial answer, as all is not understood) regarding the regulation of the urea cycle, after commenting on some of the assumptions implicit in the question.

Comments on the assumptions of the question

I am not sure that 'protein deficit' is a useful metabolic construct. From the point of view of a clinician, yes, one can say that someone is suffering from protein deficiency or malnutrition, but in metabolic terms protein is a not the highest priority and will be broken down to provide glucose for the brain during long-term starvation. And it is well established that protein synthesis is under the control of hormones and growth factors (reviewed here), and this will affect the fate of dietary amino acids or those produced by protein turnover. In addition, the emphasis on hormones in the question seems to ignore the role of the concentration of amino acids and other intermediates in regulating metabolic pathways. Finally, there is control of the expression of the genes encoding enzymes of the urea cycle, which operates over a longer time period.

The Medical Biochemistry site provides a wider perspective on amino acid metabolism and nitrogen metabolism and the urea cycle.

Regulation of the Urea Cycle

The first point that should be emphasized is that the urea cycle does not exist in isolation from other metabolic pathways, but is intimately connected to them. This is shown in the diagram below:

It should be remembered that ammonia for the urea cycle only comes from the deamination of glutamate by glutamate dehydrogenase, and the transamination of other amino acids to produce this depends on a pool of α-ketoglutarate (2-oxo glutarate). A requirement for α-ketoglutarate also exists in relation to the regeneration of aspartate for the cycle itself.

The entry point of ammonia into the urea cycle is the reaction catalysed by carbamoyl phosphate synthetase:

It turns out that this reaction requires N-acetyl glutamate (NAG) for activity, and it is thought that this plays a regulatory role in the urea cycle, as increased intake of protein has been found to increase the hepatic content of NAG. Although aspects of this remain to be clarified or resolved, it is thought that the regulation occurs at the point at which NAG is synthesized from glutamate in a reaction catalysed by the enzyme N-acetyl glutamate synthase:

This enzyme is activated by arginine, giving rise to a model for regulation described more fully in a review by Caldovic and Tuchman, from which I quote the following:

“… the hypothesis that NAG is a regulator of ureagenesis… If this hypothesis is correct, mitochondrial concentrations of glutamate and/or arginine may reflect the need for nitrogen disposal through their effect on the production of NAG by NAG synthase, glutamate as a substrate and arginine as an effector.”


Rare Disease Database

NORD gratefully acknowledges Nicholas Ah Mew, MD, Assistant Professor of Pediatrics, Children's National Medical Center, for assistance in the preparation of this report.

Synonyms of Ornithine Transcarbamylase Deficiency

  • hyperammonemia due to ornithine transcarbamylase deficiency
  • ornithine carbamyltransferase deficiency
  • OTC deficiency

General Discussion

Ornithine transcarbamylase (OTC) deficiency is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC). OTC is one of six enzymes that play a role in the break down and removal of nitrogen the body, a process known as the urea cycle. The lack of the OTC enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Excess ammonia, which is a neurotoxin, travels to the central nervous system through the blood, resulting in the symptoms and physical findings associated with OTC deficiency. Symptoms include vomiting, refusal to eat, progressive lethargy, and coma.

Signs & Symptoms

The severity and age of onset of OTC deficiency vary from person to person, even within the same family. A severe form of the disorder affects some infants, typically males, shortly after birth (neonatal period). A milder form of the disorder affects some children later in infancy. Both males and females may develop symptoms of OTC deficiency during childhood. Most carrier females are healthy, but may be prone to severe headaches following protein intake.

Children and adults with mild forms of the disorder may only have a partial OTC enzyme deficiency and therefore a greater tolerance to protein in the diet. Male infants with the severe form of the disorder often have a complete lack of the OTC enzyme.

The severe form of OTC deficiency occurs in some affected males anywhere between 24 hours to a few days after birth, usually following a protein feeding. Initial symptoms may include refusal to eat, poor suck, vomiting, progressive lethargy, and irritability. The disorder may rapidly progress to include seizures, diminished muscle tone (hypotonia), an enlarged liver (hepatomegaly) and respiratory abnormalities. Affected infants and children may also exhibit the accumulation of fluid (edema) within the brain.

If left untreated, infants with the severe form of OTC deficiency may fall into coma and may potentially develop neurological abnormalities such as intellectual disability, developmental delays, and cerebral palsy. The longer an infant remains in hyperammonemic coma the greater the chance neurological abnormalities may develop. In most cases, the longer an infant is in hyperammonemic coma the more severe these neurological abnormalities become. If left untreated, hyperammonemic coma may result in life-threatening complications.

Some infants and children may have a milder form of OTC deficiency. These infants and children may not exhibit symptoms of OTC deficiency until later during life. Children who develop OTC deficiency later during life often express the disorder during an episode of illness, and present with hyperammonemia at that time. These episodes can recur, alternating between periods of wellness.

During a hyperammonemic episode, affected children may experience vomiting, lethargy, and irritability. Additional symptoms may include confusion or delirium, hyperactivity, self-mutilation such as biting oneself, and an impaired ability to coordinate voluntary movements (ataxia). If left untreated a hyperammonemic episode may progress to coma and life-threatening complications.

OTC deficiency may not become apparent until adulthood. Adults who have OTC deficiency may exhibit migraines nausea difficulty forming words (dysarthria) an impaired ability to coordinate voluntary movements (ataxia) confusion hallucinations and blurred vision.

Causes

OTC deficiency is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. However, approximately 20% of female carriers of the OTC gene are symptomatic. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease. Many males with OTC deficiency have an abnormal OTC gene as the result of a new mutation as opposed to a mutation inherited from the mother.

Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with X-linked disorders is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

Affected Populations

OTC deficiency affects males more often than females and is fully expressed in males only. In males, symptoms typically begin during the first few days of life. Late-onset OTC deficiency can present later in childhood, but may also occur with onset at 40-50 years of age. Approximately 20% of carrier females have mild symptoms of the disorder and rarely may be severely affected in childhood. Some women who are carriers may not experience abnormally high levels of ammonia (hyperammonemia) until pregnancy or delivery.

The estimated frequency of OTC deficiency is 1/50,000 – 80,000. The estimated frequency of urea cycle disorders collectively is 1/35,000. However, because urea cycle disorders like OTC deficiency often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population.

Related Disorders

Symptoms of the following disorders can be similar to those of ornithine transcarbamylase deficiency. Comparisons may be useful for a differential diagnosis:

The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly). In some individuals, life-threatening complications may result. In addition to OTC deficiency, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency argininosuccinate synthetase deficiency (citrullinemia) argininosuccinate lyase (ASL) deficiency arginase deficiency (argininemia) and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)

Reye syndrome is a rare childhood disease characterized by liver failure, abnormal brain function (encephalopathy), abnormally low levels of glucose (hypoglycemia), and high levels of ammonia in the blood. This disorder usually follows a viral infection. It may be triggered by the use of aspirin in children recovering from chicken pox or influenza. Deficiencies of the urea cycle enzymes are thought to play a role in the development of Reye syndrome. Symptoms include vomiting, diarrhea, rapid breathing, irritability, fatigue, and behavioral changes. Neurological symptoms may be life-threatening and include seizures, stupor, and coma. (For more information on this disorder, choose “Reye” as your search term in the Rare Disease Database.)

Organic acidemias are a group of rare inherited metabolic disorders characterized by the excessive accumulation of various acids in the blood. Symptoms may include constipation, muscle weakness and low levels of platelets in the blood (thrombocytopenia). People with these disorders also have hyperammonemia and experience symptoms that are similar to those of urea cycle enzyme disorders. (For more information, choose “organic acidemia” as your search term in the Rare Disease Database.)

Diagnosis

A diagnosis of OTC deficiency should be considered in any newborn that has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability.

Blood tests may reveal excessive amounts of ammonia in the blood, the characteristic finding of urea cycles disorders. However, high levels of ammonia in the blood may characterize other disorders such as the organic acidemias, congenital lactic acidosis, and fatty acid oxidation disorders. Urea cycle disorders can be differentiated from these disorders through the examination of urine for elevated levels of organic acids and examination for alterations in plasma amino acids and plasma acylcarnitines.

The study of blood plasma and urine is used to differentiate OTC deficiency from other urea cycle disorders. Individuals with OTC deficiency usually have both low levels of citrulline and high glutamine in the blood and high levels of orotic acid in the urine.

In rare cases, OTC deficiency may be detected by surgical removal (biopsy) and microscopic examination of tissue samples from the liver, duodenum, and rectum where deficient enzyme activity may be seen.

DNA genetic testing is available to confirm the diagnosis. Mutations in the OTC gene have been identified in approximately 80% of individuals with a documented enzyme deficiency.

Carrier testing and prenatal diagnosis of OTC deficiency is possible if the disease-causing mutation has been identified in an affected family member.

Newborn screening for OTC deficiency is not currently routinely available.

Standard Therapies

Treatment of an individual with OTC deficiency may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticist, dieticians, and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech language, and physical therapists may be needed to treat children with developmental disabilities.

The treatment of OTC deficiency is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy for OTC deficiency combines dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).

Dietary restrictions in individuals with OTC deficiency are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants with OTC deficiency are placed on a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula (e.g., UCD Anamix Junior, Nutricia Cyclinex, Abbott WN1, Mead Johnson or UCD Trio, Vitaflo), and a calorie supplement without protein is often used (e.g., Pro-Phree, Abbott, PFD, Mead Johnson,). Essential amino acids supplements may also be used (EAA mix, Nutricia EAA supplement Vitaflo).

In addition to dietary restrictions, individuals with OTC deficiency are treated by medications that stimulate the removal of nitrogen from the body. These medications provide an alternative method to the urea cycle in converting and removing nitrogen waste. These medications are unpalatable to many patients and are often administered via a tube that is placed in the stomach through the abdominal wall (gastrostomy tube) or a narrow tube that reaches the stomach via the nose (nasogastric tube).

The orphan drug sodium phenylbutyrate (Buphenyl), manufactured by Hyperion Therapeutics, has been approved by the Food and Drug Administration (FDA) for the treatment of chronic hyperammonemia in OTC deficiency. In 2013, a new medication, glycerol phenylgutyrate (Ravicti), also manufactured by Hyperion Therapeutics, was approved by the FDA for treatment of chronic hyperammonemia in patients with urea cycle disorders. Ammonul (sodium phenylacetate and sodium benzoate), manufactured by Valeant Pharmaceuticals, is the only FDA-approved adjunctive therapy for the treatment of acute hyperammonemia in patients with urea cycle disorders.

Individuals with OTC deficiency benefit from treatment with arginine, or its precursor citrulline, which are needed in order to maintain a normal rate of protein synthesis. Multiple vitamins and calcium supplements may also be used in the treatment of OTC deficiency.

Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some individuals, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.

Aggressive treatment is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may be hospitalized and protein may be completely eliminated from the diet for 24 hours. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose or lipids (fat).

In cases where there is no improvement or in cases where hyperammonemic coma develops, the removal of wastes by filtering an affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children, and adults who are first diagnosed with OTC deficiency during hyperammonemic coma.

Preventive Care
After diagnosis of OTC deficiency, steps can be taken to anticipate the onset of a hyperammonemic episode. Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. In addition, elevated levels of an amino acid (glutamine) in the blood often precede the development of hyperammonemia by days or weeks. Affected individuals should receive periodic tests to measure the amount of amino acids such as glutamine in the blood. Detection of elevated levels of ammonia or glutamine may allow treatment before clinical symptoms appear. Blood tests should also be performed to monitor phenylbutyrate levels in order to assure a proper dose is used and to avoid a potential overdose.

Genetic counseling is recommended for individuals with OTC deficiency and their families.

In some cases, liver transplantation, either cadaveric or from a living donor, may be an appropriate treatment option. Liver transplantation can cure the hyperammonemia in OTC deficiency. However, this operation is risky and may result in post-operative complications. Also, after liver transplantation, patients will need to take medications life-long for immunosuppression.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

Contacts for additional information about ornithine transcarbamylase deficiency:
Nicholas Ah Mew, MD
Assistant Professor of Pediatrics
Children’s National Health System
202-476-5863 (phone)
202-476-2390 (FAX)
[email protected]

Mendel Tuchman, MD
Chief Research Officer
Scientific Director, Children’s Research Institute
Professor of Pediatrics, Biochemistry, Molecular Biology & Integrative System Biology
Children’s National Health System
202-476-2549 (phone)
202-476-6014 (FAX)
[email protected]

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      References

      TEXTBOOKS
      Adams, RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies 1997:935-37.

      Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company 1996:350-55.

      Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies 1996:12-14.

      Menkes JH, au., Pine JW, et al., eds. Textbook of Child Neurology, 5th ed. Baltimore, MD: Williams & Wilkins 1995:46-52.

      Gellis SS and Kagan BM, eds, Current Pediatric Therapy, 17th ed. Philadelphia, PA. WB Saunders, 1990.

      JOURNAL ARTICLES
      Ghabril M, Nguyen J, Kramer D, Genco T, Mai M, Rosser BG. Presentation of an acquired urea cycle disorder post liver transplantation. Liver Transpl. 2007 Dec13(12):1714-6.

      Numata S, Harada E, Maeno Y, Ueki I, Watanabe Y, Fujii C, Yanagawa T, Takenaka S, Inoue T, Inoue S, Goushi T, Yasutake T, Mizuta T, Yoshino M. Paternal transmission and slow elimination of mutant alleles associated with late-onset ornithine transcarbamylase deficiency in male patients.J Hum Genet. 200853(1):10-7. Epub 2007 Nov 20.

      Pascual JC, Matarredona J, Mut J. Acrodermatitis enteropathica-like dermatosis associated with ornithine transcarbamylase deficiency. Pediatr Dermatol. 2007 Jul-Aug24(4):394-6.

      Chiong MA, Carpenter K, Christodoulou J. Low citrulline may not be diagnostic of ornithine transcarbamylase deficiency: a case report. J Inherit Metab Dis. 2007 Jun30(3):405. Epub 2007 Apr 3.

      Nagy GR, Largiadèr CR, Nuoffer JM, Nagy B, Lázár L, Papp Z. Novel mutation in OTC gene causes neonatal death in twin brothers. J Perinatol. 2007 Feb27(2):123-4.

      Walker V. Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab. Sep 200911(9):823-35.

      Crosbie DC, Sugumar H, Simpson MA, Walker SP, Dewey HM, Reade MC. Late-onset ornithine transcarbamylase deficiency: a potentially fatal yet treatable cause of coma. Crit Care Resusc. Sep 200911(3):222-7.

      Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M. Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Hum Mutat. Jul 200627(7):626-32.

      Morioka D, Kasahara M, Takada Y, et al. Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University. Liver Transpl. Nov 200511(11):1332-42.

      Riudor E, Arranz JA, Rodes M. Partial ornithine transcarbamylase deficiency. Pediatrics. May 2003111(5 Pt 1):1123-4 author reply 1123-4.

      Lee B, et al. Long-term outcome of urea cycle disorders. J Pediatr. 2000138:S-62-S71.

      Sumi S, et al. Detection of ornithine transcarbamylase deficiency heterozygotes by measuring urinary uracil. Int J Mol Med. 20006:177-80.

      Busuttil AA, et al. The role of orthotopic liver transplantation in the treatment of ornithine transcarbamylase deficiency. Liver Transpl Surg. 19984:350-54.

      Tuchman M, et al. The biochemical and molecular spectrum of ornithine transcarbamylase deficiency. J Inherit Metab Dis. 199821:40-58.

      Tuchman M, et al. Relative frequency of mutations causing ornithine transcarbamylase deficiency in 78 patients. Hum Genet. 199697:274-76.

      Maestri NE, et al. Long-term treatment of girls with ornithine transcarbamylase deficiency. N Eng J Med. 1996335:855-59.

      Tuchman M, et al., The molecular basis of ornithine transcarbamylase deificiency: modelling the human enzyme and the effects of mutations. J Med Genet. 199532:680-8.

      Batshaw ML, Inborn errors of urea synthesis. Ann Neurol. 199435:133-41.

      Burlina AB, et al., Allopurinol challenge test in children. J Inherit Metab Dis. 199215:707-12.

      Brusilow SW, Disorders or the urea cycle. Hosp Prac. 1985305:65-72.

      INTERNET
      McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University Entry No: 311250 Last Update: 09/23/2016. Available at: http://omim.org/entry/311250 Accessed December 13, 2016.

      Roth KS, Ornithine Transcarbamylsae Deficiency. Medscape. Last Update August 28, 2015.Available at: http://emedicine.medscape.com/article/950672-overview Accessed December 13, 2016.

      Genetics Home Reference. ornithine transcarbamylase deficiency. Reviewed June2006. Available at: https://ghr.nlm.nih.gov/condition/ornithine-transcarbamylase-deficiency. Accessed December 13, 2016.

      Orphanet. Ornithine transcarbamylase deficiency. Last update: November 2015. Available at: http://www.orpha.net/consor/www/cgi-bin/OC_Exp.php?lng=EN&Expert=664 Accessed December 13, 2016.

      Years Published

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      How is the urea cycle regulated with respect to protein deficit? - Biology

      Do you have a question that you don't see listed here? Tell us!

      1. My child is suspected of having a urea cycle disorder. What tests should be performed?

      The basic tests used to help diagnose urea cycle disorders are blood ammonia, plasma amino acids and urine organic acids. These laboratory tests measure substances that reflect how well the urea cycle is working. When there is a deficiency (block) in one of the enzymes in the urea cycle, certain chemical compounds build up behind the block and others are not adequately formed beyond the block. It is like the effects of a dam. Ammonia builds up in all urea cycle disorders and should be measured. Certain amino acids are elevated in some urea cycle disorders and decreased in others, depending on where the block lies. So amino acids should be measured in plasma isolated from blood (this is a single test that at one time measures all the amino acids plasma is what is left in blood after you remove all of the red and white blood cells). Finally, urine is often needed to measure certain organic acids (primarily orotic acid and other organic acids that may affect the urea cycle). These tests are available at most Academic Medical Centers and Children's Hospitals.

      2. Does my child need a specialist or can my pediatrician treat this disorder?

      You need both. Ideally, the initial testing and the acute treatment for a urea cycle disorder should be done by a metabolic/genetic specialist experienced in treating these disorders. This metabolic specialist is often a Pediatric Geneticist and works in a hospital-based metabolic clinic that has a metabolic nutritionist, genetic counselor and social worker. This team approach offers the best chance for a good outcome. The metabolic team can then work with your pediatrician to provide ongoing care in a collaborative fashion.

      3. Is DNA testing available and/or necessary to diagnose the disorders?

      DNA testing is available for some of the disorders, but is not used as a general screening test. If the plasma amino acids and urine tests do not clearly confirm the diagnosis, more specialized testing is done. This may include obtaining blood, a skin biopsy or rarely a liver biopsy to measure the suspected missing enzyme or performing a DNA analysis on blood to identify the specific mutation or error causing the enzyme defect. These specialized tests can be obtained at an academic (university-based) medical center or Children's Hospital. These tests will usually have to be sent out for analysis, usually to one of the sites that are part of the Urea Cycle Disorders Consortium. The enzyme and DNA tests are usually done if a urea cycle disorder is strongly suspected and as yet undiagnosed. The DNA testing may also be done to help in genetic counseling of other family members, family planning, or in prenatal diagnosis.

      4. My child has been diagnosed with a urea cycle disorder. Are my other children at risk and should they be tested?

      This issue should be taken up with you metabolic specialist who can arrange any testing that is needed for your other children or yourself. Urea cycle disorders are genetic conditions therefore there may be a risk for other members in your family. However, if your child has the newborn-onset form (presenting within the first month of life) of the disorder and you have other older children who have not been symptomatic, it is most unlikely that they will be affected. Even in the late-onset form (presenting after the first month of life) of urea cycle disorders, children will usually exhibit protein intolerance and intermittent symptoms. So if you have other children who do not have clinical signs of hyperammonemia they are probably all right, but testing is available if you are worried. In the case of OTC deficiency, which is usually passed on from the mother, there may be risks for the mother's sisters or their families and testing should be arranged. This issue of risk should be taken up with your metabolic specialist or genetic counselor who can arrange any testing that is needed for your other children, yourself or other family members.

      5. My toddler has been diagnosed with a urea cycle disorder and refuses to eat sometimes, or has a temper tantrum when we try to feed him. Why is placement of a gastric tube advised for administration of medications and in case my child gets sick and will not eat?

      Many families worry about the placement of a gastrostomy tube. These tubes can be a real stress reliever for you and your child around feeding issues. It is very common for children with urea cycle disorders to have eating problems. This may include a lack of appetite, physical difficulty eating, or behavior problems. Unlike children who don't have one of these conditions, the diet of a urea cycle patient must be very carefully regulated and consistent. There are a number of reasons for the frequency of these eating problems that involve both the biology of the disease, learned behaviors, and the taste of the medicine and formula. While ideally it is best for your child to eat by mouth, this is not always possible. If he/she is not gaining weight, you find that eating issues become a negative focus of the family's life, or taking medications by mouth becomes a constant battle, the gastrostomy tube (G-tube) may be the answer. It can provide an effective alternative means of feeding and providing medication. There are certain risks in inserting and maintaining a G-tube and these should be discussed with your doctor. In general, however, children with urea cycle disorders who require G-tubes have benefited from them with improved weight gain, better metabolic contro, fewer and/or shorter hospital admissions and fewer behavior problems. These tubes are usually placed by a pediatric surgeon experienced in this procedure.

      6. My child has had periodic hyperammonemic episodes sometimes characterized by lethargy and other times hyperactivity or agitation. Why does my child exhibit these contradictory symptoms?

      The interaction between ammonia and the brain is not well understood. The elevations in ammonia and the other urea cycle-related amino acids (like glutamine) can affect different parts of the brain in different ways. Sometimes this makes a child sleepy and sometimes it makes them agitated. Both can be signs of an onset of hyperammonemia. It really depends on which part of the brain and which chemicals are affected first. In general, however, agitation and hyperactivity tend to occur prior to lethargy in a hyperammonemic episode.

      7. How high does the ammonia level have to be to cause damage to my child? At what level should my child receive treatment to lower the level?

      This is a difficult issue, and we don't really have a good answer. There appears to be a lot of individual variation. Some urea cycle patients get symptomatic at moderate ammonia levels (over 50-60 micromoles/liter) while others only become symptomatic at much higher levels (in the 100's or more). In general, the fewer the symptomatic hyperammonemic episodes, the better the developmental outcome. Also, the better the long-term metabolic control of the urea cycle disorder the better the outcome. Careful monitoring of your child's overall mental state is sometimes a more reliable measure of how they are doing. The response to a blood level of ammonia can change with the age of the child and that can also be confusing. Whenever your child becomes symptomatic or you think he may be at risk (such as during a viral illness), the metabolic team should be consulted and usually an ammonia level checked. If you can't get in touch with your metabolic specialist, take your child to the Emergency Department of the hospital that treats your child. The blood test for ammonia is difficult to perform properly and should only be done in a medical setting and laboratory experienced in the processing and handling of these samples. The ammonia level should be evaluated by a metabolic physician experienced in your child's case and urea cycle disorders. Working with you, the metabolic team can determine what treatment is best for your child. Remember that changes should only be made in close consultation with your metabolic treatment team. When you are traveling it is always useful to get the name of a metabolic physician or hospital that can treat your child if he/she gets sick.

      8. How often should my child&rsquos ammonia levels and amino acid levels be monitored?

      This should be determined by your metabolic specialist. Depending on the severity of the disease and the age of your child, this can vary from weekly to several times a year.

      9. Will my child ever grow out of this disorder or will he always have to take medications and be on a special diet?

      Your child was born with a genetic change that caused deficient or absent activity of one of the urea cycle enzymes. This absence/deficiency will remain throughout your child's life. Y our child will not "grow out" of the disease. The severity of his clinical condition , however, may change with age. We hope someday to provide a "genetic fix" for these patients but the technology is not ready yet.

      10. If protein can make my child ill, wouldn&rsquot it be better to not give him any protein at all?

      We all need some protein for our bodies to grow and repair our tissues. The restriction of protein in a urea cycle patient is a delicate clinical issue. There are many amino acids (subunits of protein) that the body cannot make on its own and must get from protein in the diet. Without these outside sources of protein and amino acids the body will break down its own protein. This break down of body protein releases ammonia which can cause hyperammonemia as bad as or worse than too much protein in the diet. Proper management of a urea cycle disorder patient involves tailoring the diet to give enough protein for growth but not more than can be handled by the broken urea cycle. This balance is difficult to achieve and changes in protein intake should be made in close consultation with the metabolic treatment team.

      11. How can you determine the difference between a hyperammonemic episode from too much protein intake as opposed to insufficient protein intake?

      This is best done by examination of the amino acid levels in the blood stream. If certain amino acids levels are low or high, your metabolic doctor can determine if the patient is breaking down protein from the body or taking too much in. Surprisingly, more patients probably become hyperammonemic from breaking down their own protein than from overdosing in their diet. This is particularly common during infections or times of stress (such as fever or decreased food intake) when the body's metabolic needs are greatest. You should discuss plans for these stressful times with your doctor before they occur.

      12. What can trigger hyperammonemic episodes?

      Anything which places increased stress on the patient can trigger an episode. Viral infections are probably the most common cause, but episodes can be triggered by physical or emotional stress, dehydration, trauma, broken bones, the menstrual cycle, certain medications (like valproic acid), and changes in the diet.

      13. My 1-year-old has just been diagnosed with a UCD. Will my child be retarded? Will my child be able to live a normal life?

      Your child with a urea cycle disorder will face many challenges in life. The outcome and the affect on their life will depend a great deal on how sick they were when they were diagnosed and how severe their defect in the cycle is. Most patients presenting with a hyperammonemic coma have some degree of delay in their development (mental retardation is defined as a measurable delay in the normal development of skills and intellect). Some of these children have delayed speech -- they start talking later than unaffected children -- or learning disabilities. Patients with severe defects in their urea cycle require treatment with many drugs and strict dietary controls. While this will complicate their daily routine, they can grow up and participate in school, play, and work. This disease does not prevent them from being loving and beloved members of their family.

      In general, children who are diagnosed after the newborn period and don't have a severe hyperammonemic crisis are less severely affected. It means that their enzyme deficiency is not a complete deficiency, and they have some capacity to get rid of ammonia. This offers some protection to the brain. These "late-onset" cases can have normal intelligence and may live a fairly normal life. They will, however, need to practice protein restriction and take medications throughout their life. While most children with late-onset urea cycle disorder are not severely mentally disabled, many have milder disabilities such as attention deficit hyperactivity disorder or learning disabilities. All patients with urea cycle disorders should probably receive some form of periodic evaluation of developmental and mental function and may greatly benefit from early interventional therapies, such as speech and occupational therapy. The Urea Cycle Disorders Consortium is conducting a long-term study to find out how well urea cycle disorder patients do with current treatment and therapies.

      14. My child has developmental delay. Will my child ever catch up to his peers?

      With developmental intervention programs and careful medical management, urea cycle patients can catch up with their peers. However, most patients who experience a severe hyperammonemic episode will have some degree of developmental delay. The duration of the hyperammonemic episode (particularly coma) does affect the outcome, with longer episodes causing worse damage to the brain. In addition to developmental delay, urea cycle patients are also at risk for milder disabilities such as attention deficit disorder or learning disabilities. If your child has a urea cycle disorder, your metabolic treatment team should arrange periodic assessment by a developmental specialist. Your child should be enrolled in an appropriate developmental intervention program at an early age based on their medical condition or developmental assessment. In some states, the therapists will come to your home and some state/federal/private insurance programs will cover these costs. These programs can really make a difference and are an important part of your child's overall treatment plan. Your metabolic treatment team will be familiar with the resources available in your area.

      15. What is the life expectancy of a child with UCD?

      We don't know the complete answer to this question. While the life expectancy of many of our most severely affected patients is shortened, new improvements in diagnosis and treatment may improve their outcome. We are currently engaged in a study to answer that question. The last study occurred almost 20 years ago when modern therapy was just being developed. The results then were not encouraging. About half of children with newborn onset disease did not survive to age 5 years. Neonatal-onset OTC and CPS1 deficiencies seemed to have a worse prognosis than the other urea cycle disorders. Many of these children are now being treated with liver transplantation (a procedure with its own serious risks and complications). Others are surviving because of improved medical management, so we believe the survival rate is much better now. The survival for the late-onset cases (presenting outside the newborn period) seems to be quite good, but there is still a significant risk of a life-threatening or debilitating hyperammonemic episode, so symptoms should always be taken seriously.

      Expanded newborn screening has helped identify urea cycle children with ASA-lyase, citrullinemia and arginase deficiency before they become seriously ill. We are seeing the outcomes for these patients in most cases being better than that of children diagnosed after they become ill. A newborn screen for OTC deficiency is being tested and, once approved, we believe will make a significant difference in saving the lives and improving the outcomes of children with OTC deficiency.

      16. We have had a child with a urea cycle disorder and want to have more children. Will subsequent pregnancies be affected? Is prenatal testing available?

      Because urea cycle disorders are genetic disorders, there is often a risk for future children having the disorder. Prenatal testing is available for all of the urea cycle disorders. Working with a metabolic specialist, a genetic counselor and your obstetrician can help you determine what type of testing is best, and when it should be done. Preimplantation Genetic Diagnosis (PGD) is available to families with identified mutations who wish to plan for more children. This involves implanting pre-selected embryos which do not have the mutation. We recommend that you contact a counselor either before you are pregnant or as soon as you know so that testing can be more easily arranged.

      17. Why isn&rsquot liver transplant recommended for all children with urea cycle disorders?

      Liver transplantation is sometimes the best therapeutic option for urea cycle patients. However, there are substantial risks to the procedure and long-term serious medical issues. The decision to transplant a urea cycle disorder patient is best made working closely with your metabolic specialist.

      18. We live in a community where we only have access to a small community hospital. Will they be able to care for my child if he has a crisis? What should we do?

      Most small community hospitals cannot deal with a major hyperammonemic episode. However, with the advent of regional patient transport systems most patients can be moved to a large hospital with the proper facilities and personnel very rapidly. With careful coordination between your metabolic specialist and local healthcare providers, many of the treatments for milder episodes and routine care can be done near your home. It is important that the hospital that treats your child has intravenous benzoate/phenylacetate (Ammonul) available in the case of a hyperammonemic crisis.

      19. Why isn&rsquot there a cure or better treatment for urea cycle disorders?

      Since urea cycle disorders are genetic diseases affecting one of the most basic pathways in the body, a cure is very difficult. The cells in the body do not have the proper instructions to make a urea cycle that works. Researchers are working on new methods to deliver healthy urea cycle genes to replace the defective ones. This may cure some patients with urea cycle diseases. Liver transplantation fixes many of the problems with urea cycle diseases but has its own side effects and consequences. We have drugs that work to help patients with urea cycle disorders but do not cure the underlying causes. Part of the work of the NUCDF is to stimulate and support research to develop and test new treatments and therapies.


      Q15.4 (POB) Positive regulation.

      A new RNA polymerase activity is discovered in crude extracts of cells derived from an exotic fungus. The RNA polymerase initiates transcription only from a single, highly specialized promoter. As the polymerase is purified, its activity is observed to decline. The purified enzyme is completely inactive unless crude extract is added to the reaction mixture. Suggest an explanation for these observations.

      Consider a hypothetical regulatory scheme in which citrulline induces the production of urea cycle enzymes. Four genes (citA, citB, citC, citD) affecting the activity or regulation of the enzymes were analyzed by assaying the wild-type and mutant strains for argininosuccinate lyase activity and arginase activity in the absence (-cit) or presence (+cit) of citrulline. In the following table, wild-type alleles of the genes are indicated by a + under the letter of the cit gene and mutant alleles are indicated by a - under the letter. The activities of the enzymes are given in units such that 1 = the uninduced wild-type activity, 100 = the induced activity of a wild-type gene, and 0 = no measurable activity. In the diploid analysis, one copy of each operon is present in each cell.

      Strain lyase activity arginase act.

      8 + + - + / + - + - 100 100 100 100

      Use the data in the table to answer the following questions.

      a) What is the phenotype of the following strains with respect to lyase and arginase activity? A single word will suffice for each phenotype.

      Lyase activity Arginase activity

      Strain 2 ______________________ ________________________

      Strain 3 ______________________ ________________________

      Strain 4 ______________________ ________________________

      Strain 5 ______________________ ________________________

      Strain 6 ______________________ ________________________

      b) What can you conclude about the roles of citBand citDin the activity or regulation of the urea cycle in this organism? Brief answers will suffice.

      c) What is the relationship (recessive or dominant) between wild-type and mutant alleles of citAand citC? Be as precise as possible in your answer.

      d) What can you conclude about the roles of citAand citCin the activity or regulation of the urea cycle in this organism? Brief answers will suffice.

      Consider a hypothetical operon responsible for synthesis of the porphyrin ring (the heterocyclic ring that is a precursor to heme, cytochromes and chlorophyll). Four genes or loci, porA, porB, porC, and porD that affect the activity or regulation of the biosynthetic enzymes were studied in a series of haploid and diploid strains. In the following table, wild-type alleles of the genes or loci are indicated by a + under the letter of the porgene or locus and mutant alleles are indicated by a &mdash under the letter. The activities of two enzymes involved in porphyrin biosynthesis, d-aminolevulinic acid synthetase and d-aminolevulinic acid dehydrase (referred to in the table as ALA synthetase and ALA dehydrase), were assayed in the presence or absence of heme (one product of the pathway). The units of enzyme activity are 100 = non-repressed activity of the wild-type enzyme, 1 = repressed activity of the wild-type enzyme (in the presence of heme), and 0 = no measurable activity. In the diploid analysis, one copy of each operon is present in each cell.

      Strain ALA synthetase ALA dehyd.

      7 - + + + / + + - + 200 101 100 100

      Use the data in the table to answer the following questions.

      a) Describe the phenotype of the following the strains with respect to ALA synthetase and ALA dehydrase activities. A single word will suffice for each phenotype.

      ALA synthetase ALA dehydrase

      Strain 2 ______________________ ________________________

      Strain 3 ______________________ ________________________

      Strain 4 ______________________ ________________________

      Strain 5 ______________________ ________________________

      Strain 6 ______________________ ________________________

      b) What is the relationship (dominant or recessive) between wild-type and mutant alleles of the four genes, and which strain demonstrates this? Please answer in a sentence with the syntax in this example: "Strain 20 is repressible, which shows that mutant grk1 is dominant to wild-type."

      porA Strain ___ is _____________, which shows that _________

      porA is _______________________________________________.

      porB Strain ___ is _____________, which shows that _________

      porB is ________________________________________________.

      porC Strain ___ is _____________, which shows that _________

      porC is ________________________________________________.

      porD Strain ___ is _____________, which shows that _________

      porD is ________________________________________________.

      c) What is the role of each of the genes in activity or regulation of porphyrin biosynthesis? Brief phrases will suffice.


      Statistics Statistics

      If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

      If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

      You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

      Healthcare Resources

      • To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from MedlinePlus Genetics.

      Notes on Phytochrome | Plant Physiology

      In plants, there is a photo reversible pigment which is called phytochrome (P), chromophoric protein, and exists in two forms: one which absorbs red (Pr) and the other one which absorbs far-red light (Pfr).

      Bestowed with such a versatility of the molecule, several bio-chemicals, physiological and morphogenetic responses can be regulated in the plants. It was in 1920 that Gardner and Allard demonstrated photoperiodism and the importance of dark period.

      Thus, short day plants failed to flower once their dark period was intercepted by a short interval of light. In 1944, Borthwick, Parker and Hendricks at the U.S. Department of Agriculture, Beltsville observed that red light (660 nm) was highly effective in inhibiting flowering of short day plants.

      On the contrary, it promoted flowering in long day plants. Same effect caused by red light was seen in stem elongation in barley and leaf growth in pea seedling grown in the dark. Earlier, Flint and Moallister (1935-37) had reported that red light highly promoted lettuce seed germination and the latter was inhibited by far-red light.

      That is far-red light exposure following red light, reversed its effects. These observations pointed towards the existence of a single photoreceptive compound which occurred in two inter-convertible forms.

      Similar situation was reported in several other phenomena. Butler used the term phytochrome for this photoreversible pigment. Norris (1959) demonstrated the photo reversibility of the pigment using a dual spectrophotometer in the cotyledons of turnip seedling.

      However, it was in 1962 that this pigment was extracted from shoots of dark grown maize seedlings and was shown to be a chromoprotein and the chromophore was a cyclic tetrapyrole. Soon after it came to be recognized that the active form was far-red absorbing (P730) and this gradually changed to P660 in the dark. The change in configuration during these reversals was also unravelled (Fig. 12-1, 2).

      Correl (1965, 1969) using analytical centrifugation studies revealed the occurrence of phytochrome tetramers which were made up of subunits. It was shown to be of similar absorption spectra. Over the years, several aspects of phytochrome chemistry have attracted attention and these are phototransformation of the pigment at low temperature in relation to subsequent dark reaction at normal temperature changes in the optical activity during photoreversibility of the pigment.

      The pigment is found to be stable between pH 6 and pH 8. The photoreversibility is gradually lost in TFA (trifloroacetic acid), DMS (dimethyl sulfamide), urea and mercapto-binders. The presence of glutaraldehyde seems to inhibit the Pr-Pfr transformation.

      Such absorption in all probability is attributed to cross linkages between the peptide chains. In a nutshell, it is imperative that chromophore is surrounded by a specific configuration of the protein.

      Indeed, studies relating to optical activity of the two forms have shed sufficient light on the role of protein moiety and also on the mechanism of photoreversibility. It is very interesting to note that in the Pr to Pfr transformation several intermediate photo-isomers are produced which are cold temperatures stable.

      Further, Pfr to Pr transformation is very simple but dark reversion of Pfr to Pr is highly temperature dependent in vitro. When oxygen is present, there is destruction. That this destruction is inhibited by EDTA. EM and ultracentrifugation techniques have shown that photoreversible part may have a dimer structure.

      Since phytochrome mediates a wide range of responses, (Table 12-2), it is difficult to propose a generalized model. By far, most efforts revolve around gene activity. Several enzyme-systems are regulated by phytochrome (nitrate reductase invertase peroxidase).

      The inhibition of enzyme synthesis by Actinomycin D or Cycloheximide following phytochrome action points towards transcription and translation. Even though possible for several systems, gene activity is unable toexplain short term responses e.g. orientation of Mougeotia chloroplast, pulvinus movement in Albizzia, etc.

      Through polarizing microscope, it is evident that this pigment is membrane localized and by changing its orientation it regulagtes membrane permeability. The general view is that chromophore component acts as a photo-receptor and undergoes cis-trans isomerization and causes change in the conformation of protein moiety.

      Thus chain of significant events is altered. However, precise mechanism of its action has been described in an oversimplified way and many questions about the mechanism of its action await detailed answers. A photo-response can be defined as phytochrome-mediated one if it could be induced by a short irradiation of red light (nearly 5 min or so, of medium quantum flux density).

      Further, the induction by red light should be reversed by far-red light. The responses may be positive or negative or may be highly complex. Then the responses may be developmental or rapid responses. The developmental responses are mediated by phytochrome but involve other physiological processes e.g., growth, differentiation and periodic phenomena. Such processes take long time for the production of a response.

      Such responses include photoperiodism, seed germination, anthocyanin formation, chlorophyll synthesis, unfolding of monocot leaves, etc. On the other hand, rapid responses are manifested in a short time after irradiation with red light and do not interact with complex physiological processes.

      This category includes orientation of chloroplast in Maugeotia filaments, leaflet, and movements in Mimosa pudica, increased permeability of water on the basis of permeability changes affected by red phytochrome, whereas developmental responses indicate an effect at gene, enzyme or hormonal level. In the following some of the phytochrome-mediated phenomenon are briefly discussed (See Table 12-2).

      (i) Phytochrome and flowering:

      The inhibition of flowering in short day plants by a red (R)- break indicates the existence of some important reactions which cause synthesis of floral stimulus. This is completed in dark. It was shown that there was involvement of a ‘light- Pfr’—’high Pfr’ reaction and a ‘low Pfr’ reaction but their sequence varies.

      During the formation of floral stimulus, there is GA-like compound synthesized. Thus, distinct ratios of P660/P730 are essential to induce flower formation.

      (ii) Chloroplast development:

      The effect of light on chloroplast development is surely mediated by phytochrome, since red illumination promotes chloroplast development and synthesis of photosynthetic enzymes.

      (iii) DNA- and Protein synthesis:

      Red light is also shown to induce DNA and protein synthesis in the cells of etiolated pea stem apices.

      In dwarf peas, R-light induced proteins which were complexed with GA3 and suggestively this complex prevented normal growth of the dwarf peas.

      (iv) Water uptake:

      Another significant effect of R-light consists of its role in regulating the uptake of different substances such as water, acetate and also exogenously applied auxins.

      (v) Seed germination/dormancy:

      In the air dried seeds of Cucurbitapepo, whole of the phytochrome exists as Pfr. On moistening of the seeds, phytochrome increased in steps as below:

      (vi) Pollen germination:

      Studies in Arachishypogaea pollen have shown that short exposure to R-light caused early tube emergence and its enhanced elongation, and that this effect was annulled by FR exposure. Obviously, the effects of R and FR were mutually reversible. Furthermore, acetylcholine and GA3 could replace the R-light effect.

      In apple, anthocyanin synthesis is regulated by the phytochrome system. M.J. Jaffe has proposed how phytochrome might affect changes in membrane permeability. His group also demonstrated that acetylcholine, the animal neurohumor, could mimic the effect of far-red light.

      These workers further proposed that acetylcholine possibly mediated several phytochrome responses in roots. There is a good possibility to believe that Red-light results in the synthesis of acetylcholine and the latter affects membranes and mitochondria and regulates the transport as well as oxygen uptake, etc.

      It is only recently that much attention is being devoted to the distribution and functions of acetylcholine in plants. H.Mohr highlighted the role of phytochrome in chloroplast development.

      From his studies a few points may be summarized below:

      The rate, at which grana appear under continuous white light saturating with respect to chlorophyll formation, is controlled by red light pulse pre-treatment.

      i. Chlorophyll a which is a characteristic marker-molecule of the plastid compartment, its formation is controlled by phytochrome.

      ii. The level of Calvin cycle enzymes is also controlled by phytochrome.

      iii. Phytochrome has also been shown to regulate photophosphorylation.

      iv. Phytochrome has also been shown to control chlorophyll b appearance.

      It is still debatable whether or not the multiple controls exerted by phytochrome during pattern realisation in plastogenesisis the result of a single initial action of Pfr or not. However, one fact is obvious that Pfr controls chloroplast development at different levels and through several independent initial actions.

      There is evidence that many of the blue-green algae (Nostocales) contain photochromic (photoreversible) pigments regulating morphogenesis, mobility and pigment synthesis. These photochromic pigments resemble the phytochrome of higher plants but have their absorption peaks at shorter wavelengths.

      In blue-green algae there is green vs. red antagonism instead of red vs far-red. As analogues of phytochrome they are referred to as cynophyceanphycochromes. Recently phycochromes a, b and c have been described. A pigment system sensing blue light (400-450 nm) and not reversible has been located in several higher and lower plants (e.g., Neurosporacrassa. Dictyostelium sp.).

      This photoreceptor may be a flavoprotein, which absorbs blue light. The reduced cytochrome gets reoxidized in dark. In Arabidopsis there are five phytochrome genes encoding five species of phytochrome (PHYA- E). Of these PhytochromeA (PHYA) accumulates in darkgrown seedlings as PrA which is stable. PfrA is unstable and is destroyed with a half-life of 1 to 1.5 hours. PHYB is expressed at low levels in both light and dark.

      PfrB is stable, with a half-life of 8-hours or more. A mixture of red and FR light will establish a photoequilibrium mixture of Pr and Pfr. Phytochrome-mediated effects are conveniently grouped into three categories on the basis of their energy requirements: very low fluence responses (VLFR), low fluence responses (LFR), and high irradiance reactions (HIR).

      LFR includes seed germination and deetiolation. VLFR are not photoreversible, is HIR requires prolonged exposure to high irradiance, are time dependent, and are not photoreversible. It seems that PHYB is the sensor that detects changes in R/FR fleucne ratio.


      Conclusions

      Interest in intermediary metabolism and the rapid improvement of analytical technologies needed to study it have never been higher. Major new findings in disease-oriented metabolic research are being reported on a weekly basis, reinforcing the concept that metabolism pervades every area of biology and pathology. The next decade promises to see continued progress in understanding the metabolic basis of common human diseases, and it is becoming increasingly feasible that some of this knowledge will be translated into novel diagnostic and therapeutic approaches, particularly in cancer.


      How is the urea cycle regulated with respect to protein deficit? - Biology

      Our editors will review what you’ve submitted and determine whether to revise the article.

      Urea, also called carbamide, the diamide of carbonic acid. Its formula is H2NCONH2. Urea has important uses as a fertilizer and feed supplement, as well as a starting material for the manufacture of plastics and drugs. It is a colourless, crystalline substance that melts at 132.7° C (271° F) and decomposes before boiling.

      What is urea?

      Urea is the chief nitrogenous end product of the metabolic breakdown of proteins in all mammals and some fishes. It occurs not only in the urine of mammals but also in their blood, bile, milk, and perspiration.

      What is the chemical name of urea?

      The chemical name of urea is carbamide, the diamide of carbonic acid. Its formula is H2NCONH2.

      Who first synthesized urea?

      German chemist Friedrich Wöhler first synthesized urea from ammonium cyanate in 1828. It was the first generally accepted laboratory synthesis of a naturally occurring organic compound from inorganic materials. Urea is now prepared commercially in vast amounts from liquid ammonia and liquid carbon dioxide.

      What is urea used for?

      Urea is used as a fertilizer and feed supplement, as well as a starting material for the manufacture of plastics and drugs.

      Urea is the chief nitrogenous end product of the metabolic breakdown of proteins in all mammals and some fishes. The material occurs not only in the urine of all mammals but also in their blood, bile, milk, and perspiration. In the course of the breakdown of proteins, amino groups (NH2) are removed from the amino acids that partly comprise proteins. These amino groups are converted to ammonia (NH3), which is toxic to the body and thus must be converted to urea by the liver. The urea then passes to the kidneys and is eventually excreted in the urine.

      Urea was first isolated from urine in 1773 by the French chemist Hilaire-Marin Rouelle. Its preparation by the German chemist Friedrich Wöhler from ammonium cyanate in 1828 was the first generally accepted laboratory synthesis of a naturally occurring organic compound from inorganic materials. Urea is now prepared commercially in vast amounts from liquid ammonia and liquid carbon dioxide. These two materials are combined under high pressures and elevated temperatures to form ammonium carbamate, which then decomposes at much lower pressures to yield urea and water.

      Because its nitrogen content is high and is readily converted to ammonia in the soil, urea is one of the most concentrated nitrogenous fertilizers. An inexpensive compound, it is incorporated in mixed fertilizers as well as being applied alone to the soil or sprayed on foliage. With formaldehyde it gives methylene–urea fertilizers, which release nitrogen slowly, continuously, and uniformly, a full year’s supply being applied at one time. Although urea nitrogen is in nonprotein form, it can be utilized by ruminant animals (cattle, sheep), and a significant part of these animals’ protein requirements can be met in this way. The use of urea to make urea–formaldehyde resin is second in importance only to its use as a fertilizer. Large amounts of urea are also used for the synthesis of barbiturates.

      Urea reacts with alcohols to form urethanes and with malonic esters to give barbituric acids. With certain straight-chain aliphatic hydrocarbons and their derivatives, urea forms crystalline inclusion compounds, which are useful for purifying the included substances.

      The Editors of Encyclopaedia Britannica This article was most recently revised and updated by Adam Augustyn, Managing Editor, Reference Content.


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      How is the urea cycle regulated with respect to protein deficit? - Biology

      The following questions or incomplete statements are in groups. Preceding each series of questions or statements is a paragraph or a short explanatory statement, a formula or set of formulas, or a definition. Read the written material and then answer the questions or complete the statements. Select the ONE BEST ANSWER for each question and indicate your selection by marking the corresponding letter of your choice on the Answer Form. Eliminate those alternatives you know to be incorrect and then select an answer from among the remaining alternatives.

      Passage I (Questions 64-66 )

      As the left ventricle of the heart contracts, it generates a pressure, which when more than that in the aorta causes the ejection of a volume of blood. The action of the ventricle can be represented as therelationship between the volume of blood in the ventricle and the intraventricularpressure. The relationship between ventricular pressure and volume is knownas the Frank-Starling law of the heart.

      During systole, the ventricle contracts, but no bloodis ejected until the pressure in the ventricle exceeds the pressure in theaorta. This phase of the cardiac cycle is known as isovolumetric contraction.When the aortic valve opens, blood is ejected without further increase inthe ventricular pressure. Therefore, this phase of contraction is isotonicand results in the ejection of a volume of blood known as the stroke volume.

      When the pressure that the ventricle can generate exactly equals the aortic pressure, the ejection of blood ceases and the ventricle undergoes isovolumetric relaxation. The blood from the atrium then fillsthe ventricle, and the pressure increase is the result of passive resistanceof the ventricle.

      64. Assuming a constant mean aortic pressure, patients with renal failure may have an increased blood volume which results in an increased end diastolic volume in the ventricle. What effect does this increase have on cardiac function?

      I. ventricular work remains constant

      II. stroke volume increases

      III. end systolic volume increases

      IV. ventricular work increases

      A. I, II, and III only C. II and IV only

      B. I and III only D. IV only

      65. Patients with hypertension have a higher mean aorticpressure. If end diastolic volume stays constant:

      I. stroke volume increases.

      II. ventricular work increases.

      III. end systolic volume decreases.

      IV. ventricular work may or may not increase.

      A. I, II, and III only C. II and IV only

      B. I and III only D. IV only

      66. With a constant mean aortic pressure and as compared to normal, a compensated failure will show:

      I. an increase in stroke volume.
      II. a stroke volume which may or may not decrease.
      III. a decrease in cardiac work.
      IV. an increase in end systolic volume. A. I, II, and III only C. II and IV only
      B.I and III only D. IV only

      Passage II (Questions 67-73)

      In a laboratory experiment, red blood cells were placed into 0.5 M solutions and the appearance of the solutions was observed two hours later with the naked eye.

      0.5 M glucose no change

      0.5 M urea hemolysis of RBCs

      0.5 M glycerol hemolysis of RBCs

      67. How can the solutions of urea and glycerol be described with respect to the red blood cells?

      B. hypotonic D. none of the above

      68. The reason for these results is that:

      I. the number of particles in the urea and glycerolsolutions is greater than that in the glucose and sucrose solutions.

      II. glucose and sucrose form coatings around the red blood cells, which prevent their breaking.

      III. glucose and sucrose enter the cells but are immediately metabolized, therefore water does not enter the cells.

      IV. urea and glycerol can enter the cell, water follows them into the cell because it is then in greater concentration outside.

      A. I and II only C III and IV only

      B. I and III only D. IV only


      69. The property of the cell membrane that allows for this phenomenon to be demonstrated is called:
      A. diffusion. C. impermeability.

      B. osmosis. D. semipermeability.

      70. The process by which a cell can move a substance from a point of lower concentration to a point of higher concentration (against the diffusion gradient) is called:

      A. osmosis C. turgor pressure
      B plasmolysis. D. active transport.

      71. Which of the following structures are NOT considered modifications of the cell membrane?


      72. The plasma membrane of animal cells:


      A. is usually rigid.
      B. has selective channels made of proteins
      C. is too thin to be seen by the use of any microscope.
      D. is composed only of proteins and carbohydrates. 73. Dialysis (as is used for the treatment of chronic kidney ailments) differs from the process of osmosis in the respect that:

      A. both solvent and solute pass through the membrane.

      B. solute selectively passes through the membrane only.

      C. solvent selectively passes through the membrane only.

      D. gases are the only substances that pass the membrane and blood is cleansed.

      Passage III (Questions 74-78)

      Enzymes have often been referred to as biological catalysts. They have many properties in common with other catalysts.

      A. carbohydrates C. lipids. B. proteins D. nucleic acids

      75. Enzymes function in reactions by:

      A. increasing the net energy yield.
      B. raising the energy level of the products.
      C. decreasing the energy of activation.
      D. changing the thermodynamic nature of a reaction, thusmaking a reaction thermodynamically favorable when it would not otherwisebe so.

      76. The nature of enzymes requires that the enzyme is:

      A. used up in quantities greater than those of substrate that is converted to product.

      B. used up in quantities approximately equal to thoseof substrate that is converted to product.

      C. used up in quantities significantly less than those of the substrate that is converted to product.

      D. essentially not used up and must be rePlacedonly in small quantities.

      77. Activity of enzymes is often regulated by covalent modification. This is most often accomplished by:

      C. substitution of one cation for another.

      D. substitution of one anion for another.

      78. The response of most enzymes to being boiled in an aqueous solution is:

      A. substantially increased activity.

      B. substantially decreased activity.

      C. an increase of about 1 unit in isoelectric point.

      D. no noticeable change is detected.

      Passage IV (Questions 79-83)

      All of the possible ketopentose sugar isomers have been synthesized in a research project. The ketopentose isomers have then been reduced with sodium borohydride, converting the ketone function to an alcohol.

      79. The total number of 2-ketopentose isomers is:

      80. The total number of isomers of the sugar alcohols produced by sodium borohydride reaction is: A. two. C. four.

      81. If all the sugar alcohols in the previous question were selectively oxidized so that the number 3 hydroxyl was converted toa ketone, there would be __________ chiral center(s) in each molecule. A. one C. three

      82. The pentose(s) found in RNA usually consists of:

      A. deoxyribose. C. various pentoses.

      83. If the sugar alcohols in question 80 were oxidized to convert carbon numbers 1 and 5 to carboxyls, the number of chiral centers would be:

      Passage V (Questions 84-87)

      The synthesis of proteins and nucleic acids is seen as being directed by a series of coded messages. The messages must be sent,received, and decoded.

      84. The primary source or repository of information concerning synthesis of nucleic acids and proteins is considered to be:
      A. protein. C. RNA.


      85. In the polymer that directs protein biosynthesis, there is a requirement of unit(s)

      (or monomers) to code for each amino acid.

      A. one C. three
      B. two D. four


      86. In a chromosome of higher animals there is(are) strand(s) of DNA.


      Watch the video: Proteiner (August 2022).