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-AminoAcidoxidase

O2 H2O

• At high levels glycine is an inhibitory neurotransmitter.

• Glycine Glyoxylate OxalateNAD NADHNH3

• 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 (CO2)

• 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 HistamineDecarboxylation(-co2)

Acid secretionİn stomach

Allergicreaction

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 T3, T4

• 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-acetylationO-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