acids and Their Biochemical Functions

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Tyrosine-Derived Neurotransmitters Tryptophan-Derived Neurotransmitters Creatine Biosynthesis

Glutathione Functions Polyamine Biosynthesis

Nitric Oxide (NO) Synthesis and Function

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Tyrosine-Derived NeurotransmittersThe majority of tyrosine that does not get incorporated into proteins iscatabolized for energy production. One other significant fate of tyrosine is

conversion to the catecholamines. The catecholamine neurotransmittersare dopamine, norepinephrine, and epinephrine (see also Biochemistryof Nerve Transmission).Norepinephrine is the principal neurotransmitter of sympatheticpostganglionic endings. Both norepinephrine and the methylatedderivative, epinephrine are stored in synaptic knobs of neurons thatsecrete it, however, epinephrine is not a mediator at postganglionicsympathetic endings.Tyrosine is transported into catecholamine-secreting neurons and adrenalmedullary cells where catechaolamine synthesis takes place. The firststep in the process requires tyrosine hydroxylase, which likephenylalanine hydroxylase requires tetrahydrobiopterin (H4B) as cofactor.The dependence of tyrosine hydroxylase on H4B necessitates the couplingto the action of dihydropteridine reductase (DHPR) as is the situation forphenylalanine hydroxylase and tryptophan hydroxylase (see below).The hydroxylation reaction generates DOPA (3,4-dihydrophenylalanine).

DOPA decarboxylase converts DOPA to dopamine, dopamine -hydroxylase converts dopamine to norepinephrine andphenylethanolamine N-methyltransferase converts norepinephrine toepinephrine. This latter reaction is one of several in the body that usesSAM as a methyl donor generating S-adenosylhomocysteine. Within thesubstantia nigra and some other regions of the brain, synthesis proceedsonly to dopamine. Within the adrenal medulla dopamine is converted tonorepinephrine and epinephrine.
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Synthesis of the catecholamines from tyrosine.

Once synthesized, dopamine, norepinephrine and epinephrine arepackaged in granulated vesicles. Within these vesicles, norepinephrineand epinephrine are bound to ATP and a protein called chromogranin A.Metabolism of the catecholemines occurs through the actions ofcatecholamine-O-methyltransferase, (COMT) and monoamine oxidase,(MAO). Both of these enzymes are widley distributed throughout the body.However, COMT is not found in nerve endings as is MAO.

back to the topTryptophan-Derived Neurotransmitters

Tryptopan serves as the precursor for the synthesis ofserotonin (5-hydroxytryptamine, 5-HT, see also Biochemistry of Nerve Transmission)and melatonin (N-acetyl-5-methoxytryptamine).
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Pathway for serotonin and melatonin synthesis from tryptophan.Abbreviations: THP = tryptophan hydroxylase, DHPR = dihydropteridinereductase, H2B = dihydrobiopterin, H4B = tetrahyrobiopterin, 5-HT = 5-

hydroxytryptophan, AADC = aromatic L-amino acid decarboxylase, SNA =serotonin N-acetylase, HOMT = hydroxyindole-O-methyltransferase.

Serotonin is synthesized through 2-step process involving atetrahydrobiopterin-dependent hydroxylation reaction (catalyzed bytryptophan-5-monooxygenase, also called tryptophan hydroxylase) and

then a decarboxylation catalyzed by aromatic L-amino aciddecarboxylase. The hydroxylase is normally not saturated and as a result,an increased uptake of tryptophan in the diet will lead to increased brainserotonin content.Serotonin is present at highest concentrations in platelets and in the

gastrointestinal tract. Lesser amounts are found in the brain and theretina. Serotonin containing neurons have their cell bodies in the midlineraphe nuclei of the brain stem and project to portions of the hypothalamus,the limbic system, the neocortex and the spinal cord. After release fromserotonergic neurons, most of the released serotonin is recaptured by anactive reuptake mechanism. The function of the antidepressant, Prozac isto inhibit this reuptake process, thereby, resulting in prolonged serotoninpresence in the synaptic cleft.


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The function of serotonin is exerted upon its interaction with specificreceptors. Several serotonin receptors have been cloned and areidentified as 5HT1, 5HT2, 5HT3, 5HT4, 5HT5, 5HT6, and 5HT7. Within the5HT1 group there are subtypes 5HT1A, 5HT1B, 5HT1D, 5HT1E, and 5HT1F.There are three 5HT2 subtypes, 5HT2A, 5HT2B, and 5HT2C as well as two

5HT5 subtypes, 5HT5a and 5HT5B. Most of these receptors are coupled toG-proteins that affect the activities of either adenylate cyclase or

phospholipase C (PLC ). The 5HT3 class of receptors are ionchannels.Some serotonin receptors are presynaptic and others postsynaptic. The5HT2A receptors mediate platelet aggregation and smooth musclecontraction. The 5HT2C receptors are suspected in control of food intakeas mice lacking this gene become obese from increased food intake andare also subject to fatal seizures. The 5HT3 receptors are present in thegastrointestinal tract and are related to vomiting. Also present in thegastrointestinal tract are 5HT4 receptors where they function in secretion

and peristalsis. The 5HT6 and 5HT7 receptors are distributed throughoutthe limbic system of the brain and the 5HT6 receptors have high affinity forantidepressant drugs.Melatonin is derived from serotonin within the pineal gland and the retina,where the necessary N-acetyltransferase enzyme is found. The pinealparenchymal cells secrete melatonin into the blood and cerebrospinalfluid. Synthesis and secretion of melatonin increases during the darkperiod of the day and is maintained at a low level during daylight hours.This diurnal variation in melatonin synthesis is brought about bynorepinephrine secreted by the postganglionic sympathetic nerves thatinnervate the pineal gland. The effects of norepinephrine are exerted

through interaction with -adrenergic receptors. This leads to increasedlevels of cAMP, which in turn activate the N-acetyltransferase required formelatonin synthesis. Melatonin functions by inhibiting the synthesis andsecretion of other neurotransmitters such as dopamine and GABA.back to the top

Creatine BiosynthesisCreatine is synthesized in the liver by methylation of guanidoacetate usingSAM as the methyl donor. Guanidoacetate itself is formed in the kidneyfrom the amino acids arginine and glycine.

Synthesis of creatine and creatinine

Creatine is used as a storage form of high energy phosphate. Thephosphate of ATP is transferred to creatine, generating creatine

phosphate, through the action of creatine phosphokinase. The reaction is
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reversible such that when energy demand is high (e.g. during muscleexertion) creatine phosphate donates its phosphate to ADP to yield ATP.

Both creatine and creatine phosphate are found in muscle, brain andblood. Creatinine is formed in muscle from creatine phosphate by anonenzymatic dehydration and loss of phosphate. The amount of

creatinine produced is related to muscle mass and remains remarkablyconstant from day to day. Creatinine is excreted by the kidneys and thelevel of excretion (creatinine clearance rate) is a measure of renal

function.back to the top

Glutathione FunctionsGlutathione (abbreviated GSH) is a tripeptide composed of glutamate,

cysteine and glycine that has numerous important functions within cells. Itserves as a reductant, is conjugated to drugs to make them more watersoluble, is involved in amino acid transport across cell membranes (the

-glutamyl cycle), is a part of the peptidoleukotrienes, serves as acofactor for some enzymatic reactions and as an aid in the rearrangement

of protein disulfide bonds.

Synthesis of glutathione(GSH)

Structure of GSSG

The role of GSH as a reductant is extremely important particularly in thehighly oxidizing environment of the erythrocyte. The sulfhydryl of GSH can
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be used to reduce peroxides formed during oxygen transport. Theresulting oxidized form of GSH consists of two molecules disulfide bondedtogether (abbreviated GSSG). The enzyme glutathione reductase utilizesNADPH as a cofactor to reduce GSSG back to two moles of GSH. Hence,

thepentose phosphate pathway is an extremely important pathway of

erythrocytes for the continuing production of the NADPH needed byglutathione reductase. In fact as much as 10% of glucose consumption, byerythrocytes, may be mediated by the pentose phosphate pathway.

Several mechanisms exist for the transport of amino acids across cellmembranes. Many are symport or antiport mechanisms that couple amino

acid transport to sodium transport. The -glutamyl cycle is an exampleof a group transfer mechanism of amino acid transport. Although this

mechanism requires more energy input, it is rapid and has a high capacity.The cycle functions primarily in the kidney, particularly renal epithelial

cells. The enzyme -glutamyl transpeptidase is located in the cellmembrane and shuttles GSH to the cell surface to interact with an amino

acid. Reaction with an amino acid liberates cysteinylglycine and generatesa -glutamyl-amino acid which is transported into the cell and hydrolyzedto release the amino acid. Glutamate is released as 5-oxoproline and thecysteinylglycine is cleaved to its component amino acids. Regeneration ofGSH requires an ATP-dependent conversion of 5-oxoproline to glutamateand then the 2 additional moles of ATP that are required during the normal

generation of GSH.back to the top

Polyamnine BiosynthesisOne of the earliest signals that cells have entered their replication cycle isthe appearance of elevated levels of mRNA for ornithine decarboxylase

(ODC), and then increased levels of the enzyme, which is the first enzymein the pathway to synthesis of the polyamines. Because of the latter, andbecause the polyamines are highly cationic and tend to bind nucleic acids

with high affinity, it is believed that the polyamines are importantparticipants in DNA synthesis, or in the regulation of that process.
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The key features of the pathway are that it involves putrescine, anornithine catabolite, and S-adenosylmethionine (SAM) as a donor of 2

propylamine residues. The first propylamine conjugation yieldsspermidine and addition of another to spermidine yields spermine.The function of ODC is to produce the 4-carbon saturated diamine,putrescine. At the same time, SAM decarboxylase cleaves the SAM

carboxyl residue, producing decarboxylated SAM (S-adenosymethylthiopropylamine), which retains the methyl group usually

involved in SAM methyltransferase activity. SAM decarboxylase activity isregulated by product inhibition and allosterically stimulated by putrescine.

Spermidine synthase catalyzes the condensation reaction, producing


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spermidine and 5'-methylthioadenosine. A second propylamine residue isadded to spermidine producing spermine.

The signal for regulating ODC activity is unknown, but since the product ofits activity, putrescine, regulates SAM decarboxylase activity, it appears

that polyamine production is principally regulated by ODC concentration.

The butylamino group of spermidine is used in a posttranslationalmodification reaction important to the process oftranslation. A specificlysine residue in the translational initiation factoreIF-4D is modified.

Following the modification the residue is hydroxylated yielding a residue inthe protein termed hypusine.

back to the topNitric Oxide Synthesis and Function

Vasodilators, such as acetylcholine and bradykinin, do not exert theireffects upon the vascular smooth muscle cell in the absence of theoverlying endothelium. When acetylcholine (or bradykinin) binds its

receptor on the surface of endothelial cells, a signal cascade, coupled to

the activation phospholipase C- (PLC ), is initiated. The PLC -mediated release of inositol trisphosphate, IP3 (from membrane

associated phosphatidylinositol-4,5-bisphosphate, PIP2), leads to therelease of intracellular stores of Ca2+. In turn, the elevation in Ca2+ leads tothe liberation ofendothelium-derived relaxing factor (EDRF) which then

diffuses into the adjacent smooth muscle. Within smooth muscle cells,EDRF reacts with the heme moiety of a soluble guanylyl cyclase, resultingin activation of the latter and a consequent elevation of intracellular levels

of cGMP. The net effect is the activation of cGMP-dependent proteinkinase (PKG) and the phosphorylation of substrates leading to smooth

muscle cell relaxation. The coronary artery vasodilator, nitroglycerin, acts

to increase intracellular release of EDRF and thus of activation of thecGMP signal cascade.

Quite unexpectedly, EDRF was found to be the free radical diatomic gas,nitric oxide, NO. So stunning was the elucidation of the pathway to andactions of NO that Drs. Murad, Ignarro and Furchgott were awarded the

Nobel Prize in 1998 for their work on this system.NO is formed by the action of NO synthase, (NOS) on the amino acid

arginine. In fact there are 3 isozymes of NOS in mammalian cells. Theseare neuronal NOS (nNOS, also called NOS-1), inducible or macrophage

NOS (iNOS, also called NOS-2), and endothelial NOS (eNOS, also calledNOS-3).

arginine -----> citrulline + NONitric oxide synthases are very complex enzymes, employing five redoxcofactors: NADPH, FAD, FMN, heme and tetrahydrobiopterin (H4B). NO

can also be formed from nitrite, derived from vasodilators such as glycerintrinitrate (nitroglycerin) during their metabolism. The half-life of NO is

extremely short, lasting only 2-4 seconds. This is because it is a highlyreactive free radical and interacts with oxygen and superoxide. NO isinhibited by hemoglobin and other heme proteins which bind it tightly.
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Both eNOS and nNOS are constitutively expressed and regulated by Ca2+.The calcium regulation is imparted be the associated calmodulin subunits,

thus explaining how vasodilators such as acetylcholine effect smoothmuscle relaxation as a consequence of increasing intracellular endothelial

cell calcium levels. Although iNOS contains calmodulin subunits, its

activity is unaffected by changes in Ca2+

concentration. iNOS istranscriptioanally activated in macrophages, neutrophils, and smoothmuscle cells.

The major functions of NO production through activation of iNOS areassociated with the bactericidal and tumoricidal actions of macrophages.

Overproduction of NO via iNOS is associated with cytokine-induced septicshock such as occurs post-operatively in patients with bacterial infections.

Bacteria produce endotoxins such as lipopolysaccharide (LPS) thatactivate iNOS in macrophages.

Nitric oxide is involved in a number of other important cellular processes inaddition to its impact on vascular smooth muscle cells. Events initiated by

NO that are important forblood coagulation include inhibition of plateletaggregation and adhesion and inhibition of neutrophil adhesion to plateletsand to the vascular endothelium. NO is also generated by cells of theimmune system and as such is involved in non-specific host defensemechanisms and macrophage-mediated killing. NO also inhibits theproliferation of tumor cells and microorganisms. Additional cellular

responses to NO include induction of apoptosis (programmed cell death),DNA breakage and mutation.

Chemical inhibitors of NOS are available and can markedly decreaseproduction of NO. The effect is a dramatic increase in blood pressure due

to vasoconstriction. Another important cardiovascular effect of NO is

exerted through the production of cGMP, which acts to inhibit plateletaggregation.back to the top

Return to Medical Biochemistry PageMichael W. King, Ph.D / IU School of Medicine / miking at iupui.edu

Last modified: Wednesday, 04-Jan-2006 14:16:22 EST
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