AA Metabolism Synthesis PDF

Medical Biochemistry II Synthesis of non-essential amino acids from TCA intermediates and essential that feed into TCA cycel SMU - Internal Data Student Learning outcomes SMU - Internal Data Methionine Valine Isoleucine Threonine Amino Acids That Form Succinyl CoA The essential amino acids methionin...

Medical Biochemistry II Synthesis of non-essential amino acids from TCA intermediates and essential that feed into TCA cycel SMU - Internal Data Student Learning outcomes SMU - Internal Data Methionine Valine Isoleucine Threonine Amino Acids That Form Succinyl CoA The essential amino acids methionine, valine, isoleucine, and threonine, are degraded to form propionyl-CoA The conversion of propionyl CoA to succinyl CoA is common to their degradative pathways SMU - Internal Data 23.11 1. Methionine: Essential AA Methionine is converted to Sadenosylmethionine (SAM), Methionine can be regenerated from homocysteine by a reaction requiring both FH4 and vitamin B12 Alternatively, by reactions requiring PLP, homocysteine can provide the sulfur required for synthesis of cysteine Carbons of homocysteine are then metabolized to a-ketobutyrate, which undergoes oxidative decarboxylation to propionyl-CoA SMU - Internal Data 2. Threonine: Essential AA Dehydrogenase SMU - Internal Data Serine/threonine Dehydratase +PLP 3. Branched chain AA The branched-chain amino acids are universal fuel, and degradation of these amino acids occurs at low levels in mitochondria of most tissues ***Note: liver cells do not have the branched chain α-keto acid dehdrogenase complex Make up almost 25% of the content of the average protein Valine and isoleucine has two major functions: energy generation and providing precursors to replenish TCA (anaplerosis) Valine and isoleucine form succinyl CoA SMU - Internal Data 3. Valine & Isoleucine The initial step in the degradation of the branched-chain amino acids is a transamination reaction Occurs often in muscle In the second step, the a-keto analogs undergo oxidative decarboxylation by the a-keto acid dehydrogenase complex The pathways for degradation of these amino acids follow parallel routes NADH and FAD(2H) are generated for energy production Isoleucine also forms acetyl CoA. SMU - Internal Data Leucine Leucine, the third branched-chain amino acid, does not produce succinyl CoA. It forms acetoacetate and acetyl CoA and is strictly ketogenic. Maple syrup urine disease: branched chain alpha-keto acid dehydrogenase is defective. Results in accumulation of branchedchain aa that appear in urine giving odor of maple syrup or burnt sugar Accumulation of the alpha-keto analogs leads to neurologic complications SMU - Internal Data Amino Acids That Form Acetyl CoA and Acetoacetate Seven amino acids produce acetyl CoA or acetoacetate → categorized as ketogenic Isoleucine, threonine, and the aromatic amino acids (phenylalanine, tyrosine, & tryptophan) are converted to both glucose and acetyl CoA or acetoacetate. Leucine and lysine do not produce glucose. SMU - Internal Data Phenylalanine and Tyrosine Phenylketonuria Phenylalanine is converted to tyrosine, which undergoes oxidative degradation The last step produces both fumarate and acetoacetate. Alcaptonuria or black urine results in the accumulation of homogentisate acid in blood and tissues. This is oxidized to alkapton that is excreted in the urine giving it a dark color. Inherited disorder SMU - Internal Data Transient Tyrosinemia Phenylketonuria Transient tyrosinemia is seen in newborn infants especially premature Likely caused by immaturity of hydroxyphenylpyruvate, enzyme Dietary restriction of protein can treat Enzyme requires ascorbate and supplementation also treats SMU - Internal Data Tyrosinemia I Phenylketonuria Tyrosinemia I (tyrosinosis) is caused by deficiency in fumarylacetoacetate hydrolase Associated with liver failure, a cabbage like body odor and death within the first year SMU - Internal Data Tyrosinemia II Phenylketonuria Tyrosinemia II is caused by a genetic deficiency of tyrosine aminotransferase (TAT) can lead to lesions in the eye and skin and neurologic problems SMU - Internal Data Phenylketonuria (PKU) Phenylketonuria Increases phenylalanine in blood Phenylalanine build up leads to brain/developmental damage Infants have musty odor Mutations in PAH gene that encodes phenylalanine hydroxylase Classic: have very low or no expression of phenylalanine hydroxylase Milder version have mutations in which the enzyme retains some activity SMU - Internal Data Autosomal recessive inheritance Alcaptonuria Phenylketonuria Black urine, black bone Accumulation of homogentisate in blood and tissues due to defect in catabolic pathway of tyrosine The is oxidized to alkapton that is excreted in the urine = dark color Homogentisic acid is removed rapidly by kidneys but accumulates over time and deposits in cartilage throughout the body Over time deposits in cartilage become slate blue Leads to early onset of osteoarthritis SMU - Internal Data Tryptophan Tryptophan is oxidized to produce alanine (from the non-ring carbons), formate, and acetyl CoA NAD and NADP can be produced from the ring structure of tryptophan Tryptophan “spares” the dietary requirement for niacin (vit. B3 + nicotinic acid) SMU - Internal Data Some genetic disorders of AA metabolism Degradation pathway Enzyme Disease Symptoms Phe Phe hydroxylase (PAH) homogentisate oxidase PKU classic alcaptonuria Mental retardation, black urine, arthritis Tyr Fumarylacetoacetate hydrolase tyrosine aminotransferase Tyrosinemia I tyrosinema II Liver failure, death, neurological damage Met Cystathionase Cystathionine β-synthase Cytathionuria homocystinemia Benign cardiovascular, neurological effects Gly Glycine transaminase (Gly è Oxaluria type 1 Renal failure Ca-oxalate stones oxalate) SMU - Internal Data Summary Following removal of amino groups, the carbon skeleton of AA undergo oxidation to compounds that enter TCA that require several cofactors including TH4, SAM in one carbon transfer reactions and BH4 in the oxidation of phenylalanine by phenylalanine hydroxylase Some AA can be converted to ketone bodies, some to glucose and some to both AA degradation is integrated into intermediary metabolism and can be critical to survival under conditions in which AA are significant source of metabolic energy SMU - Internal Data Summary Carbon skeletons of AA enter TCA cycle through five intermediates: acetyl-CoA, α-ketoglutarate succinyl-CoA, fumarate, and OAA. Some are degraded into pyruvate that can generate acetyl-CoA or OAA The following AA produce pyruvate: alanine, Cysteine Glycine Serine Threonine tryptophan The following AA produce acetyl-CoA via acetoacetyl-CoA: Leucine Lysine Phenylalanine tryptophan SMU - Internal Data Summary The following AA produce acetyl-CoA directly: Isoleucine Leucine Threonine tryptophan The following AA produce α-ketoglutarate: Arginine Glutamate Glutamine Histidine proline The following AA produce succinyl CoA SMU - Internal Data Isoleucine Methionine Threonine valine Summary The following AA produce fumarate: Phenylalanine tyrosine The following AA produce OAA: Asparagine Aspartate Branched chain AA (isoleucine, leucine and valine) unlike the other AA are degraded only in extrahepatic tissues Several serious human diseases can be traced to genetic defects in the enzymes of AA catabolism SMU - Internal Data