Glutaryl CoA

Ketone body synthesis occurs only in the mitochondrial matrix. The reactions responsible for the formation of ketone bodies are shown in Figure 24.28. The first reaction—the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA—is catalyzed by thiolase, which is also known as acetoacetyl-CoA thiolase or acetyl-CoA acetyltransferase. This is the same enzyme that carries out the thiolase reaction in /3-oxidation, but here it runs in reverse. The second reaction adds another molecule of acetyl-CoA to give (i-hydroxy-(i-methyl-glutaryl-CoA, commonly abbreviated HMG-CoA. These two mitochondrial matrix reactions are analogous to the first two steps in cholesterol biosynthesis, a cytosolic process, as we shall see in Chapter 25. HMG-CoA is converted to acetoacetate and acetyl-CoA by the action of HMG-CoA lyase in a mixed aldol-Claisen ester cleavage reaction. This reaction is mechanistically similar to the reverse of the citrate synthase reaction in the TCA cycle. A membrane-bound enzyme, /3-hydroxybutyrate dehydrogenase, then can reduce acetoacetate to /3-hydroxybutyrate. 

The degradation of pimelate is initiated by formation of the coenzyme A ester and is followed by a series of steps with the production of glutaryl-CoA that is decarboxylated to crotonyl-CoA... 

Hartel U, E Eckel, J Koch, G Fuchs, D, Linder, W Buckel (1993) Purification of glutaryl-CoA dehydrogenase from Pseudomonas sp., an enzyme involved in the anaerobic degradation of benzoate. Arch Microbiol 159 174-181. 

Isoprenoids or terpenoids are a large class of naturally occurring organic compounds with tremendous chemical and structural diversity. They are organic materials produced in the HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase pathway... 

L, loading module DH, dehydratase KS, p-ketosynthase KR, ketoreductase MT methyltransferase PS, pyran synthase DHh and KRh are DH and KR-like sequences, together with the FkbH domain, they are involved in the formation of D-lactate starter unit HMG-CS, hydroxy-methyl-glutaryl CoA synthase. Acyl-carrier-protein domains are shown as small filled balls with chain attached by the thiol group. The box shows the HMG-CS pathway for the formation of exocyclic enoate. 

Chiral 4-chloro-3-hydroxybutanoate esters are important chiral C4-building blocks [43-53]. For example, (i )- and (S)-isomers can be converted to L-car-nitine and the hydroxymethyl glutaryl-CoA reductase inhibitor. Since these compounds are used as pharmaceuticals, a high optical purity is required. A practical enzymatic method for the production of chiral 4-chloro-3-hydroxy-butanoate esters from prochiral carbonyl compounds, i.e.,4-chloroacetoacetate esters, or racemic 4-chloro-3-hydroxybutanoate esters is described. 

When asking, What do you know about hydroxy-methyl-glutaryl-CoA reductase. , it asks about the EC Number ... 

The liver meets the larger part (60%) of its requirement for cholesterol by de novo synthesis from acetylcoen-zyme-A. Synthesis rate is regulated at the step leading from hydroxymethyl-glutaryl CoA (HMG CoA) to mevalonic acid (p. 157A), with HMG CoA reductase as the rate-limiting enzyme. 

Fig. 11 Natural rubber is produced from a side branch of the ubiquitous isoprenoid pathway, with 3-hydroxy-methyl-glutaryl-CoA (HMG-CoA) as the key intermediate derived from acetyl-CoA by the general mevalonic-acid pathway. Mevalonate diphosphate decarboxylase (MPP-D) produces IPP, which is isomeiized to DMAPP by IPP isomerase (IPI). IPP is then condensed in several steps with DMAPP to produce GPP, FPP and GGPP by the action of a trani-prenyltransferase (TPT). The cA-l,4-polymeiization that yields natural rubber is catalyzed by cA-prenyltransferase (CPT), which uses the non-allylic IPP as substrate. Reprinted from [248], with permission from Elsevier...

Bok, S.H., Lee, S.H., Park, Y.B., Bae, K.H., Son, K.H., Jeong, T.S., and Choi, M.S., Plasma and hepatic cholesterol and hepatic activities of 3-hydroxy-3-methyl-glutaryl-CoA reductase and acyl CoA cholesterol transferase are lower in rats fed citrus peel extract or a mixture of citrus bioflavonoids, J. Nutr., 129, 1182, 1999. 

Hydroxy 3-methyl glutaric aciduria 3-Hydroxy 3-methyl glutaryl-CoA lyase... 

The first two reactions in the cholesterol synthetic pathway are siri lar to those in the pathway that produces ketone bodies (see Figure 16.22, p. 194). They result in the production of 3-hydroxy-3-methyl-glutaryl CoA (HMG CoA, Figure 18.3). First, two acetyl CtA molecules condense to form acetoacetyl CoA. Next, a third molecule of acetyl CoA is added, producing HMG CoA, a six-carbon compound. [Note Liver parenchymal cells contain two isoenzymes of HMG CoA synthase. The cytosolic enzyme participates in cholesterol synthesis, whereas the mitochondrial enzyme Urc tions in the pathway for ketone body synthesis.]... 

Elaborate cascades initiate the clotting of blood (Chapter 12) and the action of the protective complement system (Chapter 31). Cascades considered later in the book are involved in controlling transcription (Fig. 11-13) and in the regulation of mammalian pyruvate dehydrogenase (Eq. 17-9), 3-hydroxy-3-methyl-glutaryl-CoA reductase and eicosanoids (Chapter 21), and glutamine synthetase (Chapter 24). 

The product is hydrolyzed and oxidized to glutaryl-CoA, rejoining the pathways shown in Fig. 24-15. A remarkable and very different approach to lysine breakdown has been developed by clostridia which obtain energy from the fermentation of Eq. 24-31 ... 

Significant inhibition of all activities below pH 7 by citrate for which a Ki value of 5.2 mil/ has been observed at pH 6.5. Isocitrate much less effective, and only minor effects noted with cis-aconitate, f-malate, succinate, ar ketoglutarate, and oxalate. Malonate, tartrate, L-glutamate, glutarate, adipate, 0-hydroxy-0-methyl glutaryl-CoA, and 0-hydroxybutyrate also found ineffective as instantaneous inhibitors... 

D. A. Kleinsek, R. E. Dugan, T. A. Baker, and J. W. Porter, 3-Hydroxy-3-methyl-glutaryl-CoA reductase from rat liver, Methods Enzymol. 1981, 73, 462-479. 

Pravastatin, a 3-hydroxy-3-methyl glutaryl CoA reductase inhibitor applied as a therapeutic agent for hypercholesterolemia, can be synthesized by stereo- and regioselective hydroxylation of compactin by the soil microorganism Streptomyces sp. Y-110 (Fig. 22) [152]. The fermentative production of pravastatin has already been applied on an industrial scale by Sankyo Co. using different Streptomyces bacteria strains [153, 154]. 

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