Inherited Disorders of Amino Acid Metabolism Flashcards
Diagnosis and Treatment of Inborn Errors of Metabolism
•testing fluids
- paslma
- urine
CSF
•amino acid quantitation
-can be both, usually plasma
•organic acid quantitation
-can be both, usually urine
Metabolism of Phenylalanine and Tyrosine
- Phenylalanine, an essential amino acid, undergoes catabolism via tyrosine.
- Tyrosine is normally a non-essential amino acid, since it can be produced from phenylalanine.
-However, tyrosine becomes essential if its formation from phenylalanine is blocked.
- Note that the amino group is removed from tyrosine. This transamination has the same acceptor, alpha-ketoglutarate, as present in the alanine pathway.
- Catabolism of phenylalanine and tyrosine is accomplished in a multi-step pathway that demonstrates a number of important features common to amino acid catabolism: (1) production of organic acid intermediates, (2) requirement of a cofactor for pathway function, and (3) inborn errors of metabolism at multiple steps.
Tetrahydrobiopterin
- Tetrahydrobiopterin, the cofactor for phenylalanine hydroxylase, is regenerated from dihydrobiopterin that is reduced with NADPH via dihydropteridine reductase. T
- Tetrahydrobiopterin is also a cofactor in the hydroxylation of tyrosine to L-dopa in the synthesis of catecholamines or of pigments in different cells.
- In most cells, tyrosine is transaminated to p-hydroxyphenylpyruvate, which is further processed through a series of reactions to fumarate and acetyl CoA as endproducts.
- In adrenal medulla chromaffin and nerve cells, tyrosine is converted to L-dopa for the formation of catecholamine hormones and in skin cells, L-dopa can serve as the precursor for formation of pigment.
Disorders of Phenylalanine and Tyrosine Metabolism
- hyperphenylalaninemia
- Tyrosinemia Type II or Richard-Hanhart Syndrome
- Alkaptonuria
- Tyrosinemia Type I
- Albinism
Disorders of Phenylalanine and Tyrosine Metabolism - Hyperphenylalaninemia
- phenylketonuria
- phenylalaine hydroxylase defect —> high ;evels of phenylalanine in blood and other body fluids
- These high levels of phenylalanine are detrimental to the developing brain of children and untreated results in profound neurologic damage.
- Ninety-eight percent of cases of hyperphenylalaninemias are due to defective activity of phenylalanine hydroxylase.
- Half of the cases are due to nearly complete lack of enzyme activity—this condition is called classic phenylketonuria or PKU.
- Mutations that reduce but do not destroy enzyme activity cause milder hyperphenylalaninemia.
- The other 2% of cases are due to defects in the synthesis of tetrahydrobiopterin.
- Accumulation of phenylalanine leads to the production of unusual compounds including phenylpyruvate (formed via transamination of phenylalanine), phenyllactate (formed by reduction of phenylpyruvate) and phenylacetate (formed via oxidative decarboxylation of phenylpyruvate).
- Excretion of phenylpyruvate in the urine can be used to diagnose the disease while phenylacetate in the urine produces a “mousey” odor.
- The toxic effects of phenylalanine may be caused by reduced uptake and metabolism by the brain of other aromatic amino acids, thus reducing the synthesis of proteins.
- Deficiency of tyrosine may lead to hypopigmentation that is characterized by light skin and eyes.
Disorders of Phenylalanine and Tyrosine Metabolism - Tyrosinemia Type II or Richard-Hanhart Syndrome
- caused by a defect in tyrosine aminotransferase resulting in the elevation of blood tyrosine.
- Since the phenylalanine hydroxylase reaction is irreversible, phenylalanine levels are not increased.
- The blood tyrosine accumulates to levels exceeding the solubility of tyrosine causing tyrosine crystals to form in tissues.
- These crystals are especially evident in the cornea and palms and soles leading to corneal opacification and hyperkeratosis of the hands and feet.
- Restriction of dietary tyrosine reverses these findings.
Disorders of Phenylalanine and Tyrosine Metabolism - Alkaptonuria
- caused by an autosomal recessive defect in homogentisate oxidase that catalyzes the conversion of homogentisate to maleylacetoacetate.
- It has the distinction of being the genetic defect to which the name “inborn error of metabolism” was first applied by Sir Archibald Garrod in the early 1900s.
- Patients with alkaptonuria excrete tremendous amounts of homogentisate in the urine.
- This organic acid is also deposited in the cartilage where polymerization occurs.
-The polymer turns black leading to “black ears” and joint cartilage.
•It is also destructive and, besides the cosmetic defect, produces chronic arthritis.
Disorders of Phenylalanine and Tyrosine Metabolism - Tyrosinemia Type I
- due to a defect in fumarylacetoacetic acid hydrolase.
- This is a very severe condition that results in rapid destruction of the liver.
- It is in the differential diagnosis of liver failure in the first year of life and patients may require a liver transplant.
Disorders of Phenylalanine and Tyrosine Metabolism - Albinism
- associated with the formation of little or no skin pigment.
- Classical albinism is caused by defective tyrosinase.
- Note that this defect does not alter synthesis of catecholamine hormones because the first enzyme in that pathway is tyrosine hydroxylase.
- A variant of the disease is caused by defective tyrosine transporters decreasing the availability of tyrosine in melanocytes to make melanin.
- Decreased production of melanin increases the risk of skin cancer.
- The ocular albinism form exhibits X-linked recessive inheritance.
Metabolism of Methionine and Cysteine
•The first reaction of the pathway is the condensation of methionine with ATP resulting in the formation of the active methyl donor S-adenosylmethionine (SAM).
-This reaction is catalyzed by methionine adenosyltransferase.
- Donation of the methyl group by S-adenosylmethionine produces S-adenosylhomocysteine, which is cleaved to homocysteine and adenosine.
- Homocysteine may be converted back into methionine, however this pathway differs from the conversion of methionine to homocysteine.
- The reconversion is catalyzed by a cobalamin-containing enzyme: methionine synthase (also called 5-methyltetrahydrofolatehomocysteine methyltransferase). One of the active forms of cobalamin, methylcobalamin, donates its methyl group to homocysteine converting it to methionine
- Methylcobalamin is then regenerated from hydroxycobalamin by accepting the methyl group from N5 -methyltetrahydrofolate. Thus, both vitamin B12 (cobalamin) and folate participate in this reaction.
•Homocysteine is also metabolized to cystathionine by the enzyme cystathionine-beta-synthase , which requires pyridoxal phosphate.
-Recall pyridoxal phosphate is also a cofactor for glycogen phosphorylase and for aminotransferases (transaminases).
- Cystathionine is then cleaved to form cysteine, NH3, and alpha-ketobutyrate by the action of cystathionase.
- The cysteine produced by cystathionase is converted in a series of steps to pyruvate and sulfate.
-The majority of sulfate excreted in the urine derives from this pathway.
- alpha-Ketobutyrate undergoes oxidative decarboxylation to propionyl CoA, a three-carbon fatty acid, in a NAD-requiring reaction that also produces CO2.
- Propionyl CoA is ultimately metabolized to succinyl CoA, another endproduct of methionine metabolism.
-Succinyl CoA is also produced from isoleucine and valine.
Metabolism of Methionine and Cysteine - SAM
- The first reaction of the pathway the condensation of methionine with ATP resulting in the formation of the active methyl donor S-adenosylmethionine (SAM).
- This reaction is catalyzed by methionine adenosyltransferase.
- S-adenosylmethionine is an extremely significant compound because it donates its methyl group for the synthesis of a number of specialized compounds including creatinine, epinephrine, polyamines, phosphatidylcholine, and sphingomyelin.
-Phosphatidylcholine is found in neural membranes, and sphingomyelin is a component of the myelin sheath.
•Donation of the methyl group by S-adenosylmethionine produces S-adenosylhomocysteine, which is cleaved to homocysteine and adenosine.
Disorders of Methionine and Cysteine Metabolism
•homocystinuria
Disorders of Methionine and Cysteine Metabolism - Homocystinuria
- A defect of cystathionine-beta-synthase results in the clinical condition homocystinuria.
- A nutritional deficiency of pyridoxine, a defect in vitamin processing, or a defect in the covalent attachment of pyridoxal phosphate to the enzyme, would also increase blood levels and urinary excretion of homocystine, due to decreased activity of the synthase.
- In homocystinuria, homocysteine accumulates in the blood and is excreted in the urine where it forms a disulfide bond with another homocysteine to form homocystine.
- Homocysteine has a reactive sulfur group that enables it to form disulfide bonds with a large number of body proteins.
- Phenotypically these patients are very tall, have arachnodactyly, and exhibit dislocation of the ocular lenses.
- Most patients with homocystinuria are also mildly mentally retarded.
- Deficiency of either folate or vitamin B12 will result in homocystinuria due to reduced activity of methionine synthase.
- link to atherosclerosis?
Metabolism of Cobalamin
- Vitamin B12, cobalamin, is a critical vitamin. It is likely you will encounter disease pathology due to this vitamin, such as pernicious anemia, which is caused by nutritional deficiency or secondary malabsorption deficiency of the vitamin.
- This is somewhat surprising because there are only two known reactions that use cobalamin: the conversion of homocysteine back to methionine via methionine synthase and the conversion of methylmalonyl CoA to succinyl CoA via methylmalonyl CoA mutase.
- The forms of cobalamin used in these reactions differ. The synthase, a cytoplasmic reaction, uses methylcobalamin. The mutase, a mitochondrial reaction, uses adenosylcobalamin.
Disorders of Cobalamin Metabolism
- alterations in the production of methylcobalamin
- alterations in the production of adenosylcobalamin
defects in propionyl-CoA-carboxylase
Disorders of Cobalamin Metabolism - Methylcobalamin
- It is likely, that alterations in production of sufficient methylcobalamin cause many of the clinical signs and symptoms of vitamin B12 deficiency. This is because of the very important transfer of single carbon methyl groups.
- The methyl group from S-adenosylmethionine is used in a large number of other synthetic reactions including the formation of myelin, and homocysteine can receive a methyl group from methylcobalamin to become methionine again.
-The source of the methyl group for methyl cobalamin is N5 -methyltetrahydrofolate, which is generated from folate intermediates that get their methyl groups from a variety of sources.
- Thus, methyl groups are being transferred to and from a variety of sources, and methionine and homocysteine play a critical role in this transfer.
- If vitamin B12 is deficient, then there is accumulation of N5 -methyltetrahydrofolate causing the methyl groups to become “trapped”.
- This trap may affect a variety of pathways including DNA synthesis.
Disorders of Cobalamin Metabolism - Adenosylcobalamin
- Vitamin B12 deficiency also reduces the availability of adenosylcobalamin for methylmalonyl CoA mutase, thus leading to both methylmalonic aciduria and homocystinuria.
- Therefore, the appearance of both homocystine and methylmalonic acid in the urine is a hallmark of a primary or secondary deficiency of vitamin B12.
- A defect of methylmalonyl CoA mutase also causes methylmalonic aciduria and may be a consequence of defective binding of the adenosylcobalamin cofactor.
-In methylmalonic aciduria, propionyl CoA will accumulate, though to a lesser extent, along with the methylmalonyl CoA.
Disorders of Related to Propionyl-CoA-carboxylase
- Propionic acid is metabolically closely related to methylmalonic acid. Propionic acid (as propionyl-CoA) is converted to methylmalonic acid (as methylmalonyl-CoA).
- Propionic acid is produced from a variety of sources: the amino acids isoleucine, valine, threonine, and methionine, the catabolism of odd-chain length fatty acids, and the catabolism of the side chain of cholesterol.
- All sources of propionic acid enter the same reaction—the production of methylmalonic acid by the activity of propionyl-CoA carboxylase.
-Biotin is a cofactor for this enzyme, as it is for all carboxylases.
- Genetic mutations that destroy propionyl-CoA carboxylase activity cause propionic acidemia.
- The clinical presentation is a bit variable and patients can present with severe acidosis and neurologic signs in the neonatal period, but more typical is poor growth and feeding with developmental delays the first year of life.
- A defect of propionyl CoA carboxylase causes accumulation of propionyl CoA. Because of its abnormally high concentration, the propionyl CoA can bind to citrate synthase in place of acetyl CoA and condense with oxaloacetate to form methylcitrate.
-Methylcitrate competes with citrate for the second enzyme in the cycle and thus acts as an inhibitor of the citric acid cycle.
Metabolism of Branched Chain Amino Acids
•The branched-chain amino acids (leucine, isoleucine, valine) are essential and are biochemically similar in structure.
-Hence they share many enzymes and steps in their catabolic pathways although many steps are unique.
•The initial reaction of their catabolism is a reversible transamination in which the amino group is transferred to alpha-ketoglutarate to form glutamate and the corresponding branched-chain ketoacid (BCKA).
-Like all transaminases, the enzyme requires pyridoxine (vitamin B6). Hence a vitamin B6 deficiency will impair their metabolism.
•The second reaction is an irreversible oxidative decarboxylation, similar to pyruvate dehydrogenase, catalyzed by branched-chain ketoacid dehydrogenases (BCKADH) specific for each of the branched chain alpha-ketoacids.
- Like pyruvate dehydrogenase, BCKADH requires the same cofactors and is affected by thiamine and niacin deficiencies.
- This irreversible reaction accounts for the inability of humans to form the branched-chain amino acids from basic starting materials.
- However, the amino acids can be produced if an individual ingests the appropriate branched chain alpha-ketoacid.
- The dehydrogenases, like pyruvate dehydrogenase are comprised of three enzymatic activities (E1, E2, E3) with only the E1 component differing amongst the three enzymes.
- The subsequent reactions beyond the dehydrogenase involve a series of steps involving mostly CoA derivatives.
- Ultimately, leucine is converted to three molecules of acetyl CoA with one of the reactions being a biotin requiring carboxylase (3-methylcrotonyl-CoA carboxylase).
- Catabolism of both isoleucine and valine form succinyl CoA, though the pathways differ considerably and each produces an additional different endproduct.
-Catabolism of isoleucine, like methionine, produces propionyl CoA.
Disorders of Branched Chain Amino Acid Metabolism - MSUD
- Defects in branched chain alpha-ketoacid dehydrogenase results in a clinically important condition called maple syrup urine disease (MSUD).
- All three enzymes are affected because the defect usually resides in the E2 component that is common to decarboxylation of the three branchedchain ketoacids.
- MSUD is rare, affecting about 1:225,000 births.
- Unlike PKU, MSUD is a very dangerous disorder because the BCKAs are very toxic. Infants are born fine, feed well for the first days of life, but as the BCKAs accumulate the patient’s condition progresses from irritability to lethargy to coma over the course of the first week of life. The infant is difficult to feed, is lethargic and may vomit.
- The disease, when not treated quickly, is characterized by severe mental retardation due to brain damage, and can cause death within one year.
- Additionally, a nutritional deficiency of thiamine can produce symptoms because of the requirement of thiamine diphosphate for the reaction. The disease derives its name from the characteristic odor of the branched-chain ketoacids in the urine. Besides elevated ketoacids, the branched-chain amino acids are also elevated in the blood because the transamination reaction is reversible. Hence analysis of these amino acids, in conjunction with the clinical signs and symptoms, results in the diagnosis of MSUD.
8Because leucine, isoleucine and valine are essential amino acids, blood levels can be controlled by dietary intake. Thiamine is often supplemented to provide additionally benefit.
•MSUD is also part of the newborn screen. If identified quickly, the prognosis is good with dietary compliance, but patients with MSUD are prone to intermittent episodes of decompensation due to viral illnesses or excessive protein intake.
Disorders of Branched Chain Amino Acid Metabolism - Isovaleric Acidemia
•defective isovaleryl-CoA dehydrogenase; condition presents with acidosis, lethargy, and a urinary odor of “sweaty feet”
Disorders of Branched Chain Amino Acid Metabolism - Beta-methylcrotonylglycinuria
- defective beta-methylcrotonyl-CoA carboxylase may be asymptomatic or present with intermittent acidosis.
- The beta-methylcrotonic acid imparts a male cat urine odor and this disease is sometimes called tomcat urine disease
Disorders of Branched Chain Amino Acid Metabolism - Beta-hydroxy-beta-methylglutaryl-CoA Lyase Deficiency
- Presents with severe hypoglycemia with fasting.
- It is a cause of non-ketotic hypoglycemia.
