3-Hydroxy-3-methylglutaryl coenzyme A synthase. Evidence for an acetyl-S-enzyme intermediate and identification of a cysteinyl sulfhydryl as the site of acetylation.

Miziorko, Henry M.; Clinkenbeard, Kenneth D.; Reed, W D; Lane, M. Daniel

doi:10.1016/s0021-9258(19)41120-4

Cited by 66 publications

(54 citation statements)

References 13 publications

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“…However, the mechanism diverges at the second (condensation) step of the reaction, where the methyl group of the acetylated enzyme is activated and attacks the incoming β-keto thioester, whereas the members of the thiolase family activate a carbon of the second substrate to attack the enzyme-bound thioester . On the basis of these mutagenic studies, other kinetic studies, , and cocrystallized X-ray structures with bound intermediates, ,, one can propose the mechanism of HMG-CoA synthase that is summarized in Figure B.…”

Section: Enzymes Involved In the Cholesterol Pathwaymentioning

confidence: 99%

Cholesterol Biosynthesis: A Mechanistic Overview

et al. 2016

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Cholesterol is an essential component of cell membranes and the precursor for the synthesis of steroid hormones and bile acids. The synthesis of this molecule occurs partially in a membranous world (especially the last steps), where the enzymes, substrates, and products involved tend to be extremely hydrophobic. The importance of cholesterol has increased in the past half-century because of its association with cardiovascular diseases, which are considered one of the leading causes of death worldwide. In light of the current need for new drugs capable of controlling the levels of cholesterol in the bloodstream, it is important to understand how cholesterol is synthesized in the organism and identify the main enzymes involved in this process. Taking this into account, this review presents a detailed description of several enzymes involved in the biosynthesis of cholesterol. In this regard, the structure and catalytic mechanism of the enzymes involved in cholesterol biosynthesis, from the initial two-carbon acetyl-CoA building block, will be reviewed and their current pharmacological importance discussed. We believe that this review may contribute to a deeper level of understanding of cholesterol metabolism and that it will serve as a useful resource for future studies of the cholesterol biosynthesis pathway.

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Section: Enzymes Involved In the Cholesterol Pathwaymentioning

confidence: 99%

Cholesterol Biosynthesis: A Mechanistic Overview

et al. 2016

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“…Their binding triggers a conformational change in the C-terminal domain and flexible loop region, during which the latter covers the central domain and creates a protected catalytic pocket. Upon substrate entry, the initial isomerization step occurs, for which two different reaction routes have been proposed. ,,, …”

Section: The Methylerythritol Phosphate Pathwaymentioning

confidence: 99%

“…Upon substrate entry, the initial isomerization step occurs, for which two different reaction routes have been proposed. 14,16,19,20 The α-ketol (sigmatropic) rearrangement occurs by migration of the C3−C4 bond of DXP to form an aldehyde intermediate (Figure 7a). For this bond-formation reaction, a partial positive charge is required at C2, which can be achieved by protonation or coordination of the keto group by the metal ion.…”

Section: Dxsmentioning

confidence: 99%

“…Both enzyme catalysts form covalent adducts with their respective reaction intermediates and are cofactor-independent. HMG-CoA synthase, however, requires a water molecule for hydrolytic product release. ,− A two-step, reduced nicotinamide adenine dinucleotide phosphate- (NADPH-) dependent reduction subsequently leads to the formation of MVA and the concomitant release of CoA. The reaction is catalyzed by HMG-CoA reductase (HMGR) and follows a characteristic ping-pong mechanism of sequential CoA release and formation of a mevaldehyde intermediate.…”

Section: Introductionmentioning

confidence: 99%

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The Methylerythritol Phosphate Pathway to Isoprenoids

2016

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Isoprenoids constitute one of the most diverse classes of natural products. As a compound class, they are essential to basic metabolic processes including cell-wall biosynthesis, post-translational protein modifications, and signaling. In addition, isoprenoid secondary metabolites are highly valuable natural products with a wide range of biotechnological applications. The biosynthesis of their two universal building blocks, isopentenyl diphosphate and dimethylallyl diphosphate, was thought to proceed exclusively by way of mevalonate as a key intermediate until a novel pathway involving methylerithritol phosphate (MEP) was discovered in the early 1990s. In this review, we describe the seven enzymes of the MEP pathway, along with their discoveries, three-dimensional structures, and mechanisms. The latter include examples of remarkable enzyme catalysis including an unusual cytidilation reaction and the use of iron-sulfur cluster cofactors in reductive ring opening and hydroxy-group elimination. Furthermore, isoprenoid biosynthesis shows a characteristic species distribution. A brief overview highlights the MEP pathway's potential as a selective drug target, which is absent in humans but essential to the survival of many important bacterial and apicomplexan pathogens.

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“…The biosynthesis of terpenoids proceeds via two main biosynthetic pathways, the mevalonic acid and methylerythritol phosphate pathways . Hydroxymethylglutaryl-CoA synthase and acetyl-CoA C-acetyltransferase of the mevalonic acid pathway catalyze the condensation of acetyl-CoA and acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA, which is the precursor of isopentenyl diphosphate. The enzymes involved in the methylerythritol phosphate pathway were identified in the present study, which are responsible for the biosynthesis of dimethylallyl diphosphate .…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Lonicera japonica Thunb. Immature Flower Buds Using Combinatorial Peptide Ligand Libraries and Polyethylene Glycol Fractionation

Zhu

Tian

et al. 2015

J. Proteome Res.

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Lonicera japonica Thunb. flower is a well-known medicinal plant that has been widely used for the treatment of human disease. To explore the molecular mechanisms underlying the biological activities of L. japonica immature flower buds, a gel-free/label-free proteomic technique was used in combination with combinatorial peptide ligand libraries (CPLL) and polyethylene glycol (PEG) fractionation for the enrichment of low-abundance proteins and removal of high-abundance proteins, respectively. A total of 177, 614, and 529 proteins were identified in crude protein extraction, CPLL fractions, and PEG fractions, respectively. Among the identified proteins, 283 and 239 proteins were specifically identified by the CPLL and PEG methods, respectively. In particular, proteins related to the oxidative pentose phosphate pathway, signaling, hormone metabolism, and transport were highly enriched by CPLL and PEG fractionation compared to crude protein extraction. A total of 28 secondary metabolism-related proteins and 25 metabolites were identified in L. japonica immature flower buds. To determine the specificity of the identified proteins and metabolites for L. japonica immature flower buds, Cerasus flower buds were used, which resulted in the abundance of hydroxymethylbutenyl 4-diphosphate synthase in L. japonica immature flower buds being 10-fold higher than that in Cerasus flower buds. These results suggest that proteins related to secondary metabolism might be responsible for the biological activities of L. japonica immature flower buds.

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3-Hydroxy-3-methylglutaryl coenzyme A synthase. Evidence for an acetyl-S-enzyme intermediate and identification of a cysteinyl sulfhydryl as the site of acetylation.

Cited by 66 publications

References 13 publications

Cholesterol Biosynthesis: A Mechanistic Overview

Cholesterol Biosynthesis: A Mechanistic Overview

The Methylerythritol Phosphate Pathway to Isoprenoids

Proteomic Analysis of Lonicera japonica Thunb. Immature Flower Buds Using Combinatorial Peptide Ligand Libraries and Polyethylene Glycol Fractionation

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