Hydroxymethylglutaryl 3-

Since carotenoids are isoprenoids, they share a common early pathway with other biologically important isoprenoids such as sterols, gibberellins, phytol and the terpenoid quinones (Fig. 13.3). In all cases, these compounds are derived from the C5 isoprenoid, isopentenyl diphosphate (IPP). Until a few years ago it was believed that a single pathway from the Cg precursor mevalonic acid (MVA) formed IPP, which itself was synthesised from hydroxymethylglutaryl coenzyme A (HMG CoA) by the action of HMG... 

Further, acetoacetyI CoA becomes coupled once more to an acetyl-CoA molecule through the assistance of hydroxymethylglutaryl-CoA synthase ... 

P-Hydroxy-P-methylglutaryl-CoA is split by hydroxymethylglutaryl-CoA lyase into acetyl-CoA and acetoacetate ... 

Synthesis of endogenic cholesterol is also controlled by exogenous cholesterol supplied in food the more dietary cholesterol is digested, the less endogenic cho-lesterol is produced in the liveV. Exogenous cholesterol inhibits the activity of hydroxymethylglutaryl-CoA reductase and the cyclization of squalene to lanosterol. 

Ketone bodies are formed in the liver mitochondria by the condensation of three acetyl-CoA units. The mechanism of ketone body formation is one of those pathways that doesn t look like a very good way to do things. Two acetyl-CoAs are condensed to form acetoacetyl-CoA. We could have had an enzyme that just hydrolyzed the acetoacetyl-CoA directly to acetoacetate, but no, it s got to be done in a more complicated fashion. The acetoacetyl-CoA is condensed with another acetyl-CoA to give hydroxymethylglutaryl-CoA (HMG-CoA). This is then split by HMG-CoA lyase to acetyl-CoA and acetoacetate. The hydroxybutyrate arises from acetoacetate by reduction. The overall sum of ketone body formation is the generation of acetoacetate (or hydroxybutyrate) and the freeing-up of the 2 CoAs that were trapped as acetyl-CoA. 

GABA HMG-CoA HMPA HT LDA LHMDS LTMP NADH NBH NBS NCS NIS NK NMP PMB PPA RaNi Red-Al RNA SEM SnAt TBAF TBDMS TBS Tf TFA TFP THF TIPS TMEDA TMG TMP TMS Tol-BINAP TTF y-aminobutyric acid hydroxymethylglutaryl coenzyme A hexamethylphosphoric triamide hydroxytryptamine (serotonin) lithium diisopropylamide lithium hexamethyldisilazane lithium 2,2,6,6-tetramethylpiperidine reduced nicotinamide adenine dinucleotide l,3-dibromo-5,5-dimethylhydantoin A-bromosuccinimide A-chlorosuccinimide A-iodosuccinimide neurokinin 1 -methyl-2-pyrrolidinone para-methoxybenzyl polyphosphoric acid Raney Nickel sodium bis(2-methoxyethoxy)aluminum hydride ribonucleic acid 2-(trimethylsilyl)ethoxymethyl nucleophilic substitution on an aromatic ring tetrabutylammonium fluoride tert-butyldimcthyisilyl fert-butyldimethylsilyl trifluoromethanesulfonyl (triflyl) trifluoroacetic acid tri-o-furylphosphine tetrahydrofuran triisopropylsilyl A, N,N ,N -tetramethy lethylenediamine tetramethyl guanidine tetramethylpiperidine trimethylsilyl 2,2 -bis(di-p-tolylphosphino)-l,r-binaphthyl tetrathiafulvalene... 

HD HIV HMG hpp IL-2 IPSP hydroxydanaidal human immunodeficiency virus hydroxymethylglutaryl hours postparasitization interleukin 2 inhibitory postsynaptic potential... 

Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. The Journal of Biological Chemistry, 274, 37161-37168. 

The recent work on the stereospecificity of hydroxymethylglutaryl-CoA reductase 71 76> is particularly interesting. The reaction catalyzed by this enzyme is an important early step in the synthesis of terpenoids and steroids. The yeast enzyme and the liver enzyme both have the same stereospecificities. The overall reaction catalyzed is the reduction of hydroxymethylglutaryl CoA to mevalonic acid, as shown in scheme 1. Two molecules of NADPH are used to reduce the Co-A-bound carboxyl... 

The true biological function of liver mevaldic reductase is not clear. It is not thought to be involved in cholesterol synthesis, and because of the difference in its stereospecificity for the substrate, it is thought to be only a distant relative of the hydroxymethylglutaryl CoA reductases. But all of these enzymes have the same A stereospecifidty for the pyridine nucleotide. 

It should be noted, in this connection, that there are pyridine nucleotide dehydrogenases which catalyze redox reactions which must occur in two steps. Hydroxymethylglutaryl CoA reductase (discussed on p. 51) is one example. Another is uridine diphosphate-glucose dehydrogenase, which catalyzes the oxidation of the C—6 of the glucose (i.e., a primary alcohol) to a carboxyl group. In both cases, there are two molecules of pyridine nucleotide required, and the overall reactions are essentially irreversible. The former enzyme, with A stereospecificity for the pyridine nucleotide, catalyzes the reduction of an acyl-CoA group... 

C. R. Sirtori, Tissue Selectivity of Hydroxymethylglutaryl Coenzyme A (HMG CoA) Reductase Inhibitors , Pharmacol. Ther. 1993, 60, 431-459. 

Hydroxymethylglutaryl-CoA lyase 4.1.3.4 3-Hydroxybutyrate dehydrogenase 1.1.1.30 Nonenzymatic reaction... 

Fructose bisphosphate aldolase— aldolase Hydroxymethylglutaryl-CoA lyase Hydroxymethylglutaryl-CoA synthase Citrate synthase ATP-citrate lyase... 

HIV human immunodeficiency virus HMG-CoA hydroxymethylglutaryl coenzyme A (liver enzyme important in cholesterol metabolism)... 

Synthesis of hydroxymethylglutaryl CoA (HMG CoA) by condensation of acetoacetyl CoA with acetyl CoA is catalyzed by HMG CoA synthase and is the rate-limiting step of the pathway. 

Mechanism of Action An antihyperlipidemic that inhibits hydroxymethylglutaryl-CoA (HMG CoA) reductase, the enzyme that catalyzes the early step in cholesterol synthesis. Therapeutic Effect Decreases LDL and VLDL cholesterol, and plasma triglyceride levels increases HDL cholesterol concentration. 

Contraindications Concurrent use of a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin) in patients with active hepatic disease or unexplained persistent elevations in serum transaminase levels, moderate or severe hepatic insufficiency... 

Mechanism of Action An antihyperlipidemicthat interferes with cholesterol biosynthesis by inhibiting the conversion of the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) to mevalonate, a precursor to cholesterol. Therapeutic Effect Decreases LDL cholesterol, VLDL, and plasma triglyceride levels, increases HDL concentration. Pharmacokinetics Protein binding 88%. Minimal hepatic metabolism. Primarily eliminated in the feces. Half-life 19 hr (increased in patients with severe renal dysfunction). 

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