Conversion of Amino Acids to Specialized Products

• Biomedical Importance‐ Certain proteins contain amino acids that have been post‐translationally modified to permit them to perform specificfunctions.

‐ Examples include the carboxylation of glutamate to form ‐carboxyglutamate, which functions in Ca2+ binding, and thehydroxylation of lysine to hydroxylysine whose subsequentmodification and cross‐linking stabilizes maturing collagen fibers.

‐ certain amino acids fulfill additional roles as precursors ofbiologic materials such as heme, purines, pyrimidines, hormones,neurotransmitters, and biologically active peptides.

‐ Histamine plays a central role in many allergic reactions.

Bio. 2. ASPU. Lectu.4. Prof. Dr. F. ALQuobaili

•L‐‐Amino Acids

‐AlanineAlanine serves as a carrier of ammonia and ofthe carbons of pyruvate from skeletal muscle toliver via the Cori cycle, and together withglycine constitutes a major fraction of the freeamino acids in plasma.

‐ArginineThis figure summarizes metabolic fates of arginine. 

The guanidino group of arginine is incorporated into creatine, andfollowing conversion to ornithine, its carbon skeleton becomes that ofthe polyamines putrescine and spermine.

• Cysteine

Cysteine participates in the biosynthesis of coenzyme A byreacting with pantothenate to form 4‐phosphopantothenoyl‐cysteine.Three enzyme‐catalyzed reactions convert cysteine totaurine, which can displace the coenzyme A moiety ofcholyl‐CoA to form the bile acid taurocholic acid.The conversion of cysteine to taurine is initiated by itsoxidation to cysteine sulfinate, catalyzed by the nonhemeFe2+ enzyme cysteine dioxygenase.Decarboxylation of cysteine sulfinate by cysteine sulfinatedecarboxylase forms hypotaurine, whose oxidation byhypotaurine dehydrogenase forms taurine.

• Glycine

Metabolites and pharmaceuticals excreted as water‐soluble glycine conjugates include glycocholic acidand hippuric acid formed from the food additivebenzoate. Many drugs, drug metabolites, and othercompounds with carboxyl groups are excreted in theurine as glycine conjugates.Glycine is incorporated into creatine, and the nitrogenand ‐carbon of glycine are incorporated into thepyrrole rings and the methylene bridge carbons ofheme, and the entire glycine molecule becomes atoms4, 5, and 7 of purines.

• Histidine

Decarboxylation of histidine by the pyridoxal 5'‐phosphate‐dependent enzyme histidine decarboxylase forms histamine.Its concentration in the brain hypothalamus varies inaccordance with a circadian rhythm.Histidine compounds present in the human body includeergothioneine, carnosine, and dietary anserine.While their physiological functions are unknown, carnosine(‐alanyl‐histidine) and homocarnosine (‐aminobutyryl‐histidine) are major constituents of excitable tissues, brain,and skeletal muscle.Urinary levels of 3‐methylhistidine are unusually low inpatients withWilson's disease.

• Methionine

The major nonprotein fate of methionine is conversion to S ‐adenosylmethionine, the principal source of methyl groupsin the body.S ‐Adenosylmethionine is synthesized from methionine andATP, a reaction catalyzed by methionine adenosyltransferase(MAT). Human tissues contain three MAT isozymes (MAT‐1and MAT‐3 of liver and MAT‐2 of nonhepatic tissues).Although hypermethioninemia can result from severelydecreased hepatic MAT‐1 and MAT‐3 activity, if there isresidual MAT‐1/MAT‐3 activity and MAT‐2 activity is normal, ahigh tissue concentration of methionine will assure synthesisof adequate amounts of S‐adenosylmethionine.

Following decarboxylation of S‐adenosylmethionine bymethionine decarboxylase, three carbons and the ‐aminogroup of methionine contribute to the biosynthesis of thepolyamines spermine and spermidine.

• These polyamines function in cell proliferationand growth, are growth factors for culturedmammalian cells, and stabilize intact cells,subcellular organelles, and membranes.Pharmacologic doses of polyamines arehypothermic and hypotensive.

• This figure summarizes catabolism ofpolyamines.

• Serine

Serine participates in the biosynthesis of sphingosine, and of purines and pyrimidines, where it provides carbons 2 and 8 of purines and the methyl group of thymine. Conversion of serine to homocysteine is catalyzed by cystathionine ‐synthase:

Serine + homocysteine  Cystathionone + H2O

• Tryptophan

Following hydroxylation of tryptophan to 5‐hydroxytryptophan by liver tyrosine hydroxylase, subsequentdecarboxylation forms serotonin (5‐hydroxytryptamine), apotent vasoconstrictor and stimulator of smooth musclecontraction. Catabolism of serotonin is initiated bymonoamine oxidase‐catalyzed oxidative deamination to 5‐hydroxyindole‐3‐acetate.N‐Acetylation of serotonin followed by its O‐methylation inthe pineal body forms melatonin.Kidney tissue, liver tissue, and fecal bacteria all converttryptophan to tryptamine, then to indole 3‐acetate.The principal normal urinary catabolites of tryptophan are 5‐hydroxyindoleacetate and indole 3‐acetate.

• Tyrosine

‐ Neural cells convert tyrosine to epinephrine andnorepinephrine. While dopa is also anintermediate in the formation of melanin,different enzymes hydroxylate tyrosine inmelanocytes.

‐ Dopa decarboxylase, a pyridoxal phosphate‐dependent enzyme, forms dopamine. Subsequenthydroxylation by dopamine ‐oxidase then formsnorepinephrine. In the adrenal medulla,phenylethanolamine‐N‐methyltransferase utilizesS‐adenosylmethionine to methylate the primaryamine of norepinephrine, forming epinephrine.

• Phosphoserine,Phosphothreonine,&Phosphotyrosine

The phosphorylation and dephosphorylation of specific seryl,threonyl or tyrosyl residues of proteins regulate the activity ofcertain enzymes of lipid and carbohydrate metabolism.

• Sarcosine (N‐Methylglycine)The biosynthesis and catabolism of sarcosine (N‐methyl¬glycine)occur in mitochondria. Formation of sarcosine from dimethyl‐glycine is catalyzed by the flavoprotein dimethylglycine dehydro‐genase, which requires reduced pteroylpentaglutamate (TPG).

Dimethylglycine + FADH2 + H4 TPG + H2O   Sarcosine + N‐formyl‐TPG

Traces of sarcosine can also arise by methylation of glycine, areaction catalyzed by S‐adenosylmethionine:glycinemethyltransferase.

Glycine + S‐Adenosylmethionine Sarcosine +S‐Adenosylhomocysteine

Catabolism of sarcosine to glycine, catalyzed by the flavoproteinsarcosine dehydrogenase, also requires reduced TPG:

Sarcosine+FAD+H4 TPG+H2O Glycine+FADH2+N‐formyl‐ TPG

• Creatine & CreatinineCreatinine is formed in muscle from creatine phosphate byirreversible, nonenzymatic dehydration and loss of phosphate.Glycine, arginine, and methionine all participate in creatinebiosynthesis. Synthesis of creatine is completed bymethylation of guanidoacetate by S‐adenosylmethionine.

• Non‐‐Amino AcidsNon‐‐amino acids present in tissues in a free form include ‐alanine, ‐aminoisobutyrate, and ‐aminobutyrate (GABA).‐Alanine is also present in combined form in coenzyme A and inthe ‐alanyl dipeptides carnosine, anserine and homocarnosine.

• Alanine & ‐Aminoisobutyrate ‐Alanine and ‐aminoisobutyrate are formed duringcatabolism of the pyrimidines uracil and thymine,respectively. Traces of ‐alanine also result from thehydrolysis of ‐alanyl dipeptides by the enzyme carnosinase.The initial reaction of ‐alanine catabolism is transaminationto malonate semialdehyde. Subsequent transfer ofcoenzyme A from succinyl‐CoA forms malonyl‐CoAsemialdehyde, which is then oxidized to malonyl‐CoA anddecarboxylated to the amphibolic intermediate acetyl‐CoA.

The ‐alanyl dipeptides carnosine and anserine (N ‐methylcarnosine) activate myosin ATPase, chelate copper, andenhance copper uptake.Biosynthesis of carnosine is catalyzed by carnosine synthetasein a two‐stage reaction that involves initial formation of anenzyme‐bound acyl‐adenylate of ‐alanine and subsequenttransfer of the ‐alanyl moiety to L‐histidine.

ATP + ‐Alanine‐Alanyl‐ AMP + PPi‐Alanyl‐ AMP + L‐ Histidine Carnosine + AMP

Hydrolysis of carnosine to ‐alanine and L ‐histidine is catalyzedby carnosinase. The heritable )بالوراثة ينتقل( disorder carnosinasedeficiency is characterized by carnosinuria.Homocarnosine, present in human brain at higher levels thancarnosine, is synthesized in brain tissue by carnosine synthetase.

‐Aminobutyrate

‐Aminobutyrate (GABA) functions in brain tissue asan inhibitory neurotransmitter by alteringtransmembrane potential differences. GABA isformed by decarboxylation of glutamate by L ‐glutamate decarboxylase .Transamination of ‐aminobutyrate formssuccinate semialdehyde, which can be reduced to ‐hydroxybutyrate by L ‐lactate dehydrogenase, or beoxidized to succinate and thence via the citric acidcycle to CO2 and H2O.

Summary• In addition to serving structural and functional roles in

proteins, α‐amino acids participate in a wide variety ofother biosynthetic processes.

• Arginine provides the formamidine group of creatine andthe nitrogen of nitric oxide (NO). Via ornithine, arginineprovides the skeleton of the polyamines putrescine,spermine and spermidine.

• Cysteine provides the thioethanolamine portion ofcoenzyme A, and following its conversion to taurine, part ofthe bile acid taurocholic acid.

• Glycine participates in the biosynthesis of heme, purines,creatine, and N‐methylglycine (sarcosine). Many drugs anddrug metabolites are excreted as glycine conjugates, whichincreases water solubility for urinary excretion.

• Decarboxylation of histidine forms the neurotransmitterhistamine. Histidine compounds present in the human body include ergothioneine, carnosine, and dietary anserine. 

• S‐Adenosylmethionine, the principal source of methylgroups in metabolism, contributes its carbon skeleton to the biosynthesis of the polyamines spermine and spermidine. 

• In addition to its roles in phospholipid and sphingosinebiosynthesis, serine provides carbons 2 and 8 of purines and the methyl group of thymine. 

• Key tryptophan metabolites include serotonin and melatonin. Kidney and liver tissue, and also fecal bacteria, convert tryptophan to tryptamine and thence to indole 3‐acetate, The principal tryptophan catabolites in urine are indole 3‐acetate and 5‐hydroxyindoleacetate. 

• Tyrosine forms norepinephrine and epinephrine, and followingiodination the thyroid hormones triiodothyronine and thyroxine.

• The enzyme‐catalyzed interconversion of thephospho‐ and dephospho‐forms of peptidebound serine, threonine and tyrosine plays keyroles in metabolic regulation, including signaltransduction.

• Glycine, arginine, and S‐adenosylmethionine allparticipate in the biosynthesis of creatine, whichas creatine phosphate serves as a major energyreserve in muscle and brain tissue. Excretion inthe urine of its catabolite creatine is proportionateto muscle mass.

• ‐Alanine and ‐aminoisobutyrate both are presentin tissues as free amino acids. ‐Alanine also occursin bound form in coenzyme A, carnosine, anserine,and homocarnosine. Catabolism of ‐alanine involvesstepwise conversion to acetyl‐CoA. Analogousreactions catabolize ‐aminoisobutyrate to succinyl‐CoA. Disorders of ‐alanine and ‐aminoisobutyratemetabolism arise from defects in enzymes ofpyrimidine catabolism.

• Decarboxylation of glutamate forms the inhibitoryneurotransmitter ‐aminobutyrate (GABA). Two rare metabolic disorders are associated with defects in GABA catabolism.