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Part2 dental Amino Acid Metabolism 2012-1


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Part2 dental Amino Acid Metabolism 2012-1

  2. 2. Catabolism of Carbon Chains From Amino Acids
  3. 3. Deaminated Amino acids yield α-keto acids that, directly or via additional reactions, feed into major metabolic pathways (e.g., Krebs Cycle). Carbon skeletons of glucogenic amino acids are degraded to: - pyruvate, or - a 4-C or 5-C intermediate of Krebs Cycle. These precursors are major carbon source for gluconeogenesis when glucose levels are low. They can also be catabolized for energy, or converted to glycogen or fatty acids for energy storage. Carbon skeletons of ketogenic amino acids are degraded to: -acetyl-CoA, or -acetoacetate. can be catabolized for energy in Krebs Cycle, or converted to ketone bodies or fatty acids. They cannot be converted to glucose. Glucogenic amino acids The 3-C α-keto acid pyruvate is produced from alanine, serine, glycine, cysteine, & threonine. Alanine deamination via Transaminase directly yields pyruvate. alanine -ketoglutarate pyruvate glutamate Aminotransferase (Transaminase) COO CH2 CH2 C COO O CH3 HC COO NH3 + COO CH2 CH2 HC COO NH3 + CH3 C COO O+ +
  4. 4. Glutamate -Ketoglutarate + + Pyruvate Alanine Glutamate-Pyruvate Aminotransferase (Alanine Transferase ALT) synthesis Glucose-Alanine Cycle
  5. 5. Serine is deaminated to pyruvate via Serine Dehydratase. Serine can be also catabolized (in reverse of its biosynthesis but different enzymes) into 3-phosphoglycerate . HO CH2 H C COO NH3 + C COO OH2O NH4 + C COO NH3 + H2C H3C H2O serine aminoacrylate pyruvate Serine Dehydratase
  6. 6. Threonine is catabolized ,through β-ketobutyrate by threonine dehydrogenase, into pyruvate . Threonine is catabolized -but to less extent- by Ser/Thr dehydratase into α-ketobutyrate to be converted to propionyl CoA then to succinyl CoA. In addition to ketogenic catabolism into acetyl CoA and glycine. Formation of Serine OHH CH2OPO3 -2 C CO2 - CH2OPO3 -2 CO 2 - C=O NH3 +H CH2OPO3 -2 C CO2 - NH3 +H CH2OH CO2 - C Glucose Glycolysis 3-Phospho- glycerate 3-Phospho- hydroxypyruvate 3-PhosphoserineSerine (Ser) Pyruvate Dehydrogenase NAD+ NADH + H+ Glutamate α Ketoglutarate Transaminase Phosphatase 3 Steps Inhibits
  7. 7. Glycine is also a product of threonine catabolism through α-amino-β-ketobutyrate (as just shown). It is interconverted to serine by a reversible reaction involving tetrahydrofolate producing N5,N10-THF (determined by demands for serine or glycine or availability of N5,N10-THF).
  8. 8. Glycine can also be degraded to CO2 and NH3 by a glycine cleavage complex whose deficiency leads to the mental disorder Nonketotic hyperglycinemia. Glyoxalate produced by glycine can be transaminated back to glycine or oxidized to oxalate which at high level could lead to kidney stones. Cysteine is synthesized from methionine. Methionine adenosyltransferase catalyzes the formation of S- adenosylmethionine which loses a methyl and adenosyl group by methyltransferase and adenosylhomocysteinase ,respectvely, to form homocysteine. However, only sulfur atom of homocysteine will transfer to a serine to form cysteine after formation of the adduct cystathionine and its cleavage by cystathionase into cysteine and α-ketobutyrate .
  9. 9. NH3 + CH3SCH2CH2CHCO2 - NH3 + HSCH2CH2CHCO2 - NH3 + CH2CHCO2 - NH3 + SCH2CH2CHCO 2 -NH3 + HSCH2CHCO2 - OH CH3CHCH2CO2 - Methionine (Essential) L-Homocysteine Methionine Synthase (Vit. B12-dep.) + FH4 + 5-Methyl FH4 NH3 +H CH2OH CO2 - C Serine Cystathionine Cystathionine -synthase (PLP-dep.) Cystathionine lyase Cysteine (Non-essential) + -Hydroxy- butyrate H3C S H2 C H2 C H C COO NH3+CH2 + O OHOH HH HH Adenine H3C S H2 C H2 C H C COO NH3+ HS H2 C H2 C H C COO NH3+ S H2 C H2 C H C COO NH3+CH2 O OHOH HH HH Adenine methionine homocysteine S-adenosyl- methionine (SAM) S-adenosyl- homocysteine ATP PPi + Pi adenosine H2O acceptor methylated acceptor THF N5 -methyl-THF
  10. 10. Cystathioninuria Deficiency in cystathionase (lyase) No clinical symptoms (↑cystathionine in blood & urine) Homocysteinuria • Rare; deficiency of cystathionine β-synthase • Dislocated optical lenses • Mental retardation • Osteoporosis • Cardiovascular disease death High blood levels of homocysteine associated with cardiovascular disease • May be related to dietary folate deficiency • Folate enhances conversion of homocysteine to methionine Cysteine catabolism yields pyruvate.
  11. 11. The 4-C Krebs Cycle intermediate oxaloacetate is produced from aspartate & asparagine. Aspartate transamination yields oxaloacetate. Aspartate is also converted to fumarate in Urea Cycle. Fumarate is converted to oxaloacetate in Krebs cycle. aspartate -ketoglutarate oxaloacetate glutamate Aminotransferase (Transaminase) COO CH2 CH2 C COO O COO CH2 HC COO NH3 + COO CH2 CH2 HC COO NH3 + COO CH2 C COO O+ +
  12. 12. Glutamate -Ketoglutarate + + Oxaloacetate Aspartate Glutamate-Oxaloacetate Aminotransferase (Aspartate Transferase AST) synthesis Asparagine loses the amino group from its R-group by hydrolysis catalyzed by Asparaginase. This yields aspartate, which can be converted to oxaloacetate, e.g., by transamination. C CH2 HC COO NH3 + OH2N COO CH2 HC COO NH3 + H2O NH4 + asparagine aspartate Asparaginase
  13. 13. ATP-dependent amidation of Asp  ASP + ATP + GLN  ASN + AMP + PPi + GLU By the enzyme Asparagine synthetase. Low in some cell tumor types. ( Asparaginase treatment ) . The 4-C Krebs Cycle intermediate succinyl-CoA is produced from isoleucine, valine, & methionine. Transulfuration reactions of methionine ,that synthesize cysteine from homocysteine and serine, produce α-ketobutyrate which is converted to propionyl CoA, which is metabolized into succinyl-CoA through unusual reactions one of which is vitamin B12 dependent . Valine and isoleucine in addition to leucine are branched-chain amino acids (BCAAs). Their metabolism is an excellent source of energy (NADH). Initial steps : BCAA transferases α-keto counterparts α-keto acid dehydrogenases CoA compounds dehydrogenases double bond compounds Valine and isoleucine form hydroxylated intermediate. The isoleucine intermediate is oxidized by NAD into succinyl CoA and acetyl CoA . The valine intermediate is oxidized by NAD in another step into succinyl CoA.
  14. 14. The 5-C Krebs Cycle intermediate a-ketoglutarate is produced from glutamate, glutamine, arginine, proline , & histidine. O - O2CCH2CH2CCO 2 - NH3 + - O2CCH2CH2CHCO 2 - NH3 +O H2NCCH2CH2CHCO 2 - Transamination or Glutamate dehydrogenase -Keto- glutarate Glutamate Glutamine Glutamine synthetase N H H CO2 - + Proline NH3 + + H3NCH2CH2CH2CHCO 2 - Ornithine 5 Steps Intest. mucusa Arginine Urea Cycle (or through citrulline in kidney) NH3 +NH2 H2N=C-HNCH2CH2CH2CHCO 2 - + Amino Acids Formed From α-Ketoglutarate 4 Steps via glutamic semialdehyde Glutamate deamination via transaminase directly yields a-ketoglutarate. Glutamate deamination by Glutamate Dehydrogenase also directly yields α-ketoglutarate.  OOC H2 C H2 C C COO O + NH4 + NAD(P)+ NAD(P)H  OOC H2 C H2 C C COO NH3 + H glutamate -ketoglutarate Glutamate Dehydrogenase aspartate -ketoglutarate oxaloacetate glutamate Aminotransferase (Transaminase) COO CH2 CH2 C COO O COO CH2 HC COO NH3 + COO CH2 CH2 HC COO NH3 + COO CH2 C COO O+ +
  15. 15. GABA Formation NH3 + - O2CCH2CH2CHCO 2 - NH3 + - O2CCH2CH2CH2 Glutamate Gamma-aminobutyrate (GABA) GABA is an important inhibitory neurotransmitter in the brain Drugs (e.g., benzodiazepines) that enhance the effects of GABA are useful in treating epilepsy Glutamate decarboxylase CO2 Glutamine is catabolized into glutamate by glutaminase. Creatine and Creatinine Arginine Phosphocreatine N N H CH3 HN O Creatinine (Urine) Non-enzymatic (Muscle) NH2 CH3 H2N=C-NCH2CO2 - + Creatine kinase (Muscle) ATP Creatine ADP + Pi
  16. 16. Proline and Arginine are catabolized into α-ketoglutarate but in slightly different pathway than their synthesis. Histidine is converted to glutamate. The first step is catalyzed by histadinase. The last step in this pathway involves the cofactor tetrahydrofolate. Histidinemia is caused by histidinase deficiency. Mental retardation (not always)(↑histidine in blood) (& urine). Histidine Metabolism: Histamine Formation N N H CH2CHCO2 - NH3 + N N H CH2CH2NH2 Histidine Histamine Histidine decarboxylase CO2 HC C CH2 H C COO NH3 +N NH C H  OOC H C CH2 CH2 COO HN NH C H  OOC H C CH2 CH2 COO NH3 + THF N 5 -formimino-THF NH4 + H2O H2O histidine N-formimino- glutamate glutamate
  17. 17. Aromatic Amino Acids Aromatic amino acids phenylalanine & tyrosine are catabolized to fumarate and acetoacetate. Hydroxylation of phenylalanine to form tyrosine involves the reductant tetrahydrobiopterin. Some tyrosine is used to synthesize catecholamines : DOPA (dihydroxyphenylalanine) and Dopamine (related to Parkinson’s disease) in brain , Norepinephrine and Epinephrine in adrenal medulla, in synthetic order :- CH2 CH COO NH3 + CH2 CH COO NH3 + HO phenylalanine tyrosine O2 + tetrahydrobiopterin H2O + dihydrobiopterin Phenylalanine Hydroxylase
  18. 18. CH2CHCO2 - NH3 + HO CH2CHCO2 - NH3 + HO HO CH2CH2NH2 HO HO CHCH2NH2 HO HO OH CHCH2NHCH3 HO HO OH Tyr hydroxylase O2 Tyrosine Dihydroxyphenylalanine (DOPA) Dopamine DOPA decarboxylase CO2 Dopamine hydroxylase Norepinephrine Catechol Epinephrine (Adrenaline) SAM S-Adenosyl- homocysteine Methyl transferase Genetic deficiency of Phenylalanine Hydroxylase leads to the disease Phenylketonuria (PKU). Phenylalanine & phenylpyruvate (the product of phenylalanine deamination via transaminase) accumulate in blood & urine. Mental retardation results unless treatment begins immediately after birth. Treatment consists of limiting phenylalanine intake to levels barely adequate to support growth. Tyrosine, an essential nutrient for individuals with phenylketonuria, must be supplied in the diet. • Occurs in 1:16,000 live births in U.S. • Seizures, mental retardation, brain damage • Treatment: limit phenylalanine intake • Screening of all newborns mandated in all states Transaminase Phenylalanine Phenylpyruvate (Phenylketone) Phenylalanine Deficient in Hydroxylase Phenylketonuria Tyrosine Melanins Multiple Reactions Fumarate + Acetoacetate
  19. 19. High [phenylalanine] inhibits Tyrosine Hydroxylase (tyrosinase), on the pathway for synthesis of the pigment melanin from tyrosine. Therefore, individuals with phenylketonuria have light skin & hair color. Conversion of tyrosine to melanin requires tyrosinase or tyrosine hydroxylase in melanocytes whose defect or absence leads to Albinism . Transaminase Phenylalanine Phenylpyruvate (Phenylketone) Phenylalanine Deficient in Hydroxylase Phenylketonuria Tyrosine Melanins Multiple Reactions Fumarate + Acetoacetate
  20. 20. Homogentisic Acid Formation CH2CHCO2 - NH3 + HO OH OH CH2CO2 - Transamination Tyrosine Homogentisate O2 CO2 CH2CCO2 - O HO Homogentisate dioxygenase O2 Cleavage of aromatic ring Fumarate + acetoacetate Deficient in alkaptonuria Tyrosinemia Deficiency of tyrosine transaminase leads to diffferent diseases including: Eye, skin and mental retardation liver failure, renal dysfunction, rickets, and neuropathy Alkaptonuria (first metabolic inborn error identified) • Deficiency of homogentisate dioxygenase • Urine turns dark on standing • Oxidation of homogentisic acid • Asymptomatic in childhood • Tendency toward arthritis in adulthood (Cartilage deposition)
  21. 21. Tryptophan Tryptophan has complex pathways for degradation. kynurenine is formed and can be further metabolized into glutarate then acetoacetyl CoA. Kynurenine can give rise to neurotransmitters. Typtophan hydroxylation then decarboxylation end up with the brain neurotransmitter serotonin. The sleep-inducing molecule Melatonin is synthesized from tryptophan. Ingestion of tryptophan rich food leads to sleepiness due to melatonin sleeping effect. ketogenic amino acids The only two entirely ketogenic amino acids are Leucine and Lysine As explained earlier for the other branched-chain amino acids (BCAAs) valine and isoleucine they share with leucine initial steps of catabolism that form a double bond CoA compound. However, leucine gives an intermediate which is cleaved to acetoacetate and acetyl CoA. Diseases of metabolism of BCAAs Enzyme deficiency is not common. Rare hypervalinemia and hyperleucinemia-isoleucinemia. Deficiency in ketoacid dehydrogenases leads to maple syrup urine disease, mental retardation, ketoacidosis, and short life span. Enzyme deficiency of later reactions gives sweaty feet urine smell, and cat urine smell.
  22. 22. Lysine has ( as tryptophan) a complex pathways for degradation into acetoacetyl CoA. Hyperlysinemia is benign . More serious is familial lysinuric protein intolerance due to failure in intestinal transport that leads to decrease in plasma lysine, arginine and ornithine down to 1/3 normal, with after meal hyperammonemia related to urea cycle. Other glucogenic amino acids that are have ketogenic fate include: The aromatic amino acids phenylalanine and tyrosine that generate acetoacetate, and tryptophan which produces acetoacetyl CoA (as we saw earlier). That is in addition to the BCAA isoleucine shown to form acetyl CoA . And finally threonine which forms acetyl CoA and glycine through α-amino-β-ketobutyrate mentioned earlier. END Metabolic Defects in Amino Acid Metabolism 1. Hereditary deficiency of any of the Urea Cycle enzymes leads to hyperammonemia 2. Nonketotic hyperglycinemia 3. Oxalate kidney stones 4. Cystathioninuria 5. Homocysteinuria 6. Histidinemia 7. Hyperphenylalaninemias- Phenlketoneuria (PKU) 8. Albinism 9. Tyrosinemia 10. Alcaptouria 11. BCAA metabolic diseases 12. Lysine metabolic diseases