Catabolism of Carbon Skeletons of AAs Prof. Dr. Arzu SEVEN

The pathways of amino acid catabolism normally accounts for only 10-15% of human body's energy production. 20 catabolic pathways converge to form only 6 major products, all of which enter citric acid cycle. From there, C skeletons are diverted to gluconeogenesis or ketogenesis or are completely oxidized to CO2 and H2O.

Amino acids may be either glucogenic or ketogenic. These amino acids that feed carbons into TCA cycle at the level of α-ketoglutarate, succinyl coA, fumarate or oxaloacetate and those that produce pyruvate,can produce glucose via gluconeogenesis and are glucogenic (alanine, arginine, asparagine,aspartic acid, glycine, histidine, methionine, proline, serine, valine)

Those amino acids that feed carbons at the level of acetyl-coA or acetoacetyl coA are ketogenic (leucine, lysine)

Leucine is an exclusively ketogenic AA,its degradation makes a substantial contribution to ketosis under starvation Both glucogenic and ketogenic AAs isoleucine, phenylalanine, threonine, tryptophan, tyrosine

Amino acids that we can not synthesize are termed ESSENTİAL amino acids

Cysteine is not generally considered as an essential AA because it can be derived from non-essential amino acid serine, its sulfur must come from essential amino acid methionine. Tyrosine is not required in the diet, but must be derived from essential amino acid phenylalanine.

Conversion of AA to Specialized Products Important products derived from AA include heme, purines, pyrimidines, hormones, neurotransmitters and biologically active peptides.

Glycine Water-soluble glycine conjugates: glycocholic acid and hippuric acid formed from food additive benzoate. Drugs or drug metabolites with carboxyl groups are excreted in the urine as glycine conjugates.

Creatine and glutathione Nitrogen and α-C of glycine are, incorporated into the pyrole rings and methylene bridge carbons of heme. 4,5, and 7 atoms of purine glycine is degraded via 3 pathways:

Nonketotic hyperglycinemia: Defect in glycine cleavage enzyme activity Glycine (serum) mental deficiency death in early childhood

D-Amino Acid oxidase O 2 H 2 O At high levels glycine is an inhibitory neurotransmitter. Glycine Glyoxylate Oxalate NAD NADH NH 3

Primary function of D-amino acid oxidase, present at high levels in the kidney, is to detoxify the ingested D-amino acids derived from bacterial cell walls and from grilled foodstuff. Oxalate, from food or produced enzymatically in kidney, has medical significance as crystals of calcium oxalate in 75% of kidney stones. (urolithiasis, nephrocalcinosis, early mortality from renal failure or hypertension)

Several enzyme cofactors play important roles in amino acid catabolism: Transamination requires pyridoxal phosphate One Carbon transfer requires Biotin tetrahydrofolate and S-adenosylmethionine

Biotin transfers Carbon its most oxidized state (CO 2 ) Tetrahydrofolate transfers one carbon groups in intermediate oxidation states (as methyl groups) s-adenosylmethionine transfers methyl groups (the most reduced state of carbon)

Homocystinuria A relatively rare autosomal recessive condition Defect in methionine catabolism Lack of an enzyme which catalyzes the transfer of sulfur from homocysteine to serine though the formation of cystathionine intermediate. Mental retardation, vision problems, thrombotic strokes, coronary artery disease at young age.

Defective carrier-mediated transport of cystine results in cystinosis (cystine storage disease) with deposition of cystine crystals in tissues and early mortality from acute renal failure. In cystinuria,a defect in renal reabsorption,cystine,lysine,arginine and ornithine are excreted. The mixed disulfide of L-cysteine and L- homocysteine,excreted by cystinuric patients,is more soluble and reduces formation of cystine calculi.

β-Alanine: β-alanine, a metabolite of cysteine, is present in coenzyme A and as B- alanyLdipeptides (carnosine, anserine ) Cysteine: A precursor of thioethanol amine portion of coenzyme A A precusor of taurine that conjugates with bile acids such as taurocholic acid

Histidine Histidin Histamine Decarboxylation (-co 2 ) Acid secretion İn stomach Allergic reaction vasodilatator

Arginine: Formamidine donor for creatine synthesis Precursor of nitric oxide, NO (neurotransmitter, smooth muscle relaxant and vasodilatator)

Phosphocreatine, derived from creatine, is an important energy buffer in skeletal muscle. Creatine is synthesized from glycine, arginine. Methionine, in the form of S_adenosylmethionine, acts as a methyl donor.

Tryptophan, lysine, phenylalanine, tyrosine, leucine, isoleucine and threonine acetyl coA and/or aceto acetyl -coA Tryptophan: Nicotinamide Serotonin indolacetate

Principal normal urinary catabolites of tryptophan are 5-hydroxyindolacetate and indole-3-acetate.

Phenylalanine Tyrosine Dopamine NE E T 3, T 4 Melanin is derived from tyrosine

Parkinson's disease is associated with underproduction of dopamine.It has traditonally been treated by L-Dopa administration. Over production of dopamine in the brain may be linked to schizophrenia.

5 hydroxytryptamine=serotonin: A potent vasoconstrictor and stimulator of smooth muscle contraction.

Serotonin 5 hydroxy indolacetate melatonin MAO Catalyzed oxidative deamination N-acetylation O-methylation

Carcinoid(argentaffinoma) Tm cells that over produce serotonin.

Glutamate decarboxylation gives rise to GABA, an inhibitory neurotransmitter Its overproduction is associated with epilectic seizures. GABA analogs are used in the treatment of epilepsy and hypertension.

γ-aminobutyrate (GABA) Functions in the brain as an inhibitory neurotransmitter by altering transmembrane potential differences. L-glutamate GABA decarboxylase

Branched Chain AA (leucine, valine, isoleucine) are oxidized as fuels primarily in muscle, adipose, kidney and brain tissue (extrahepatic tissues)

1-Transamınation (branced-chain amino transferase (absent in liver) 2-Oxidative decarboxylation (by mitochondrial branched chain α-ketoacid dehydrogenase) α- AA α- ketoacid

This multimeric enzyme complex resembles pyruvate dehydrogenase and α-ketoglutarate dehydrogenase being inactivated by phosphorylation and activated by dephosphrylation. 5 cofactors (TPP, FAD, NAD, lipoate, coenzyme A) 3-Dehydrogenation