Conversion of Amino acids into Non-protein Nitrogenous Compounds

Dr. Contessa S. Tac-an

Glycine
‡ Heme synthesis ‡ Synthesis of purines forms positions 4, 5, 7 of the purine ring ‡ Constituent of glutathione ‡ Conjugates with cholic acid to form glycocholic acid ‡ Conjugates with benzoic acid to form hippuric acid ‡ Synthesis of creatine

Alanine
‡ Carnosine - is a ß-alanyl dipeptide that occurs in human skeletal muscle. ‡ Anserine - also a ß-alanyl dipeptide - derived from the diet - occurs in skeletal muscle characterized by rapid contractile activity.

Structure of Carnosine

Structure of Anserine

Carnosine & Anserine
Functions: 1. Activate myosin ATPase activity. 2. Chelate copper and enhance copper uptake.

Cont.
Synthesis:
Carnosine synthetase

ß-alanine + L-histidine + ATP €€€p Carnosine + AMP + PPi
Carnosine N-methyltransferase

Carnosine + SAM €€€€€€€p SAH + Anserine

Cont.
Degradation:
Carnosinase

Carnosine €€€p ß-Alanine + LHistidine ‡ Carnosinase deficiency - heritable d/o characterized by persistent carnosinuria.

Homocarnosine
‡ CNS dipeptide ‡ Related structurally &metabolically to carnosine but is present in human brain at levels 100x higher than carnosine levels ‡ Synthesis in brain tissue is catalyzed by carnosine synthetase

Structure of Homocarnosine

Serine, threonine & tyrosine
‡ Phosphorylation (by protein kinases) & dephosphorylation (by protein phosphatases) of ser, thr & tyr serve important regulatory functions.

Serine
‡ Biosynthesis of sphingosine ‡ Purines & pyrimidines pp ß-carbon of ser provides methyl groups of thymine (& of choline) and of carbons 2 & 8 of purines.

Methionine
‡ Its activated form, SAM (S-adenosyl methionine) is the principal source of methyl groups in the body. ‡ Biosynthesis of 3-diaminopropane portions of the polyamines, spermine and spermidine.

Cysteine
‡ Urinary sulfate arises from the oxidation of L-cysteine. (Sulfur of methionine contributes to urinary SO4 indirectly, via cysteine. ‡ Precursor of thioethanolamine portion of CoA ‡ Converted to Taurine, that conjugates with bile acids such as taurocholic acid

Histidine
‡ Decarboxylation of histidine forms histamine, catalyzed by aromatic Lamino acid decarboxylase or histidine decarboxylase. ‡ Other histidine compounds include: ergothioneine, carnosine, and dietary anserine.

Synthesis of Histamine

Structure of ergothioneine

Arginine
‡ Arginine - formamidine donor for creatine synthesis ‡ Conversion, via ornithine, to putrescine, spermine & spermidine. ‡ Precursor of nitric oxide (NO), w/c is a neurotransmitter, smooth muscle relaxant & vasodilator.

Arginine
NO synthase

L-Arginine + O2 + NADPH €€€€p L-Citrulline + NO ‡ Precursor of polyamines, spermine
And spermidine, w/c function in cell proliferation and growth.

Spermine & Spermidine
‡ Growth factors for cultured cells. ‡ Stabilization of intact cells, subcellular organelles & membranes. ‡ Pharmacologic doses of polyamines are hypothermic and hypotensive. ‡ Associate w/ polyanions such as DNA & RNA ‡ Stimulate DNA & RNA synthesis

Cont.
‡ DNA stabilization ‡ Packaging of DNA in bacteriophage ‡ Exert diverse effects in protein synthesis ‡ Inhibit protein kinases Polyamine biosynthesis catalyzed by ornithine decarboxylase.

Polyamine biosynthesis
‡ L-ornithine - precursor of putrescine portion of spermine & spermidine SAM - precursor of diaminopropane portion

‡

Cont.
Enzymes: 1. Ornithine decarboxylase & SAM decarboxylase - inducible enzymes w/ short half-lives 2. Spermine & Spermidine synthases - are neither inducible nor unusually labile enzymes.

Ornithine decarboxylase
‡ Half life 10 mins. ‡ Ten- to 200-fold increase in its activity after administration to cultured cells of GH, corticosteroids, testosterone or EGF

SAM decarboxylase
‡ Cofactor: pyruvate ‡ Half life 1-2 hours ‡ Responds to promoters of cell growth ‡ Inhibited by decarboxylated SAM ‡ Activated by putrescine

Polyamine degradation
‡ Polyamine oxidase, of liver peroxisomes, oxidizes spermine to spermidine; subsequently oxidizes spermidine to putrescine. ‡ Putrescine oxidizes to NH4 + CO2. ‡ Both aminopropane is converted to ßaminopropionaldehyde. Major fraction of putrescine & spermidine are excreted in urine as conjugates (acetyl derivatives).

Tryptophan
‡ Forms serotonin Synthesis/Reactions: 1. Hydroxylation of trp to 5-OHtrp, catalyzed by liver tyrosine hydroxylase 2. Decarboxylation of 5-OHtrp forms serotonin(5-hydroxytryptamine)

Synthesis of Serotonin

Serotonin
‡ Potent vasoconstrictor ‡ Stimulator of smooth muscle contraction ‡ Catabolism initiated by monoamine oxidase-catalyzed oxidative deamination to 5hydroxyindoleacetate, excreted in the urine (2-8mg/d)

Cont.
‡ Malignant carcinoid increases serotonin production. ‡ Catabolites detected in the urine include N-acetylserotonin glucuronide and 5hydroxyindoleaceturate. ‡ Reduced synthesis of niacin (Vit. B3), causing pellagra.

Serotonin forms melatonin
Reactions: ‡ N-acetylation ‡ O-methylation Melatonin - taken up by all tissues (incl. brain); rapidly metabolized by hydroxylation at position 6, then conjugated w/ SO4 or glucuronic acid.

Trp metabolites
‡ Excreted in urine and feces ‡ Principal normal urinary catabolites are 5-hydroxyindoleacetate and indole-3-acetate.

Tyrosine
‡ Biosynthesis of melanins, catalyzed by tyrosine hydroxylase. ‡ Neuronal cells convert tyrosine to epinephrine and norepinephrine ‡ Dopamine synthesis, via dopa decarboxylase (B6PO4 as cofactor) ‡ Norepinephrine synthesis catalyzed by dopamine ß-oxidase(Vit. C and copper dependent enzyme) ‡ Methylation of NE (adrenal medulla) catalyzed by phenylethanolamine-Nmethyltransferase, forms epinephrine ‡ Precursor of T3 and T4.

Synthesis of cathecolamines

ALBINISM
‡ ‡ Defective melanin biosynthesis Hypomelanosis due to heritable defects in eye and skin melanocytes ‡ Oculocutaneous albinism ‡ Forms: 1. Tyrosine hydoxylase negative albinos ± lack all visual pigment -- hair bulbs fail to convert tyrosine to pigment; melanocytes contain unpigmented melanosomes

Cont.
2. Tyrosine hydroxylase positive albinos ± w/ some visible pigment & white-yellow to light tan hair. -- melanocytes w/ lightly pigmented melanosomes. 3. Ocular albinism ± AR & X-linked trait. X-linked ocular albinism ±retinas w/ mosaic pattern of pigment distribution.

Creatine biosynthesis
‡ Derived from glycine, arginine & methionine ‡ Transfer of guanidino group from arginine to glycine, forming guanidoacetate(glycocyamine); occurs in kidney ‡ Methylation of guanidoacetate by SAM in the liver

Cont.
‡ Creatine and phosphocreatine are present in muscle, brain & blood. ‡ Forms creatinine (creatine anhydride) in muscle, from creatine PO4 by dehydration & loss of phosphate ‡ 24 hr creatinine excretion in urine is constant from day to day & proportionate to muscle mass

L-glutamate
‡ Biosynthesis of K-Aminobutyrate (GABA), via decarboxylation of Lglutamate catalyzed by glutamate decarboxylase(B6PO4 cofactor) present in CNS ‡ Addtition: Putrescine can be converted to GABA, either by deamination (by diamine oxidase) or via N-acetylated intermediates.

Cont.
‡ GABA degradation
GABA transaminase

GABA €€€€€p succinate semialdehyde ‡ Succinate semialdehyde may undergo either: 1. Reduction to K-hydroxybutyrate 2. Oxidation to succinate to CO2 & H2O

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