3-Hydroxy-3-methylglutaryl-CoA Reductase

Rodwell, Victor W.; Beach, M. J.; Bischoff, Kenneth M.; Bochar, Daniel A.; Darnay, Bryant G.; Friesen, Jon A.; Gill, John F.; Hedl, Matija; Jordan-Starck, Tuajuanda C.; Kennelly, Peter J.; Kim, Dong Yul; Wang, Yuli

doi:10.1016/s0076-6879(00)24237-7

Cited by 31 publications

(21 citation statements)

References 22 publications

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“…Conserved domain database research has shown that the conserved domain 'HMG-coenzyme A (HMG-CoA)_reductase_classI' is located at positions 441-847. This domain is responsible for catalysing the conversion of HMG-CoA to mevalonate, a four-electron oxidoreduction that is the rate-limiting step in the synthesis of cholesterol and other isoprenoids (Rodwell et al, 2000;Friesen & Rodwell, 2004). The highly conserved catalytic portion possesses amino acids involved in the binding of HMG-CoA (ENVIGYMPVP at positions 504-513, TTEGCLVV at positions 533-540) and NADPH (DAMGMNMV at positions 628-635, TIGGGT at positions 780-785).…”

Section: Resultsmentioning

confidence: 99%

3‐hydroxy‐3‐methyl glutaryl coenzyme A reductase: an essential actor in the biosynthesis of cantharidin in the blister beetle Epicauta chinensisLaporte

Jiang

Huo

et al. 2015

Insect Molecular Biology

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Cantharidin (C(10)H(12)O(4)) is a monoterpene defensive toxin in insects involved in chemical defence as well as in courtship and mating behaviours. It is relatively well known in the medical literature because of its high anticancer activity and as an effective therapy for molluscum contagiosum. However, little is known about its biosynthesis pathway in vivo, and no enzyme involved in cantharidin biosynthesis has been identified. The purpose of this study was to identify the crucial enzyme that is involved in the biosynthesis of cantharidin. Using the homology cloning method, a 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) gene, the rate-limiting enzyme in the mevalonate pathway, was cloned from the blister beetle Epicauta chinensis. Quantitative reverse transcription PCR and gas chromatography methods revealed that the HMGR transcripts had a positive correlation with cantharidin production in the beetles (R = 0.891). RNA interference (RNAi) knockdown of HMGR mRNA expression was achieved by microinjection of a specific double-stranded RNA with more than 90% RNAi efficiency, and an apparent decrease of cantharidin production was observed. Furthermore, the HMGR mRNA was greatly upregulated by exogenous juvenile hormone III (JH III), and cantharidin production was also raised in males; however, when injecting the JH III with RNAi of HMGR mRNA at the same time, cantharidin production did not rise. These results demonstrate that HMGR is an essential enzyme in cantharidin biosynthesis in the blister beetle E. chinensis, which further verifies previous research results demonstrating that cantharidin is synthesized de novo by the mevalonate pathway in blister beetles.

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Section: Resultsmentioning

confidence: 99%

3‐hydroxy‐3‐methyl glutaryl coenzyme A reductase: an essential actor in the biosynthesis of cantharidin in the blister beetle Epicauta chinensisLaporte

Jiang

Huo

et al. 2015

Insect Molecular Biology

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“…Protein Expression and Purification-Following expression in E. coli of the mvaA gene that encodes P. mevalonii HMG-CoA reductase, the enzyme was purified to homogeneity as described previously (1).…”

Section: Methodsmentioning

confidence: 99%

“…Present in all known organisms, isoprenoids function in processes as diverse as maintenance of membrane structure, cell wall and glycoprotein synthesis, defense mechanisms, and modification of proteins and tRNAs. Formation of isopentenyl diphosphate can occur by either of two pathways: the mevalonate pathway (1) or the glyceraldehyde 3-phosphate-pyruvate (GAPpyruvate) pathway (2). Animals and Archaea use only the mevalonate pathway, and plants utilize both pathways (2)(3)(4).…”

mentioning

confidence: 99%

Crystal Structure of a Statin Bound to a Class II Hydroxymethylglutaryl-CoA Reductase

Tabernero

Rodwell

Stauffacher

2003

Journal of Biological Chemistry

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Hydroxymethylglutaryl-CoA (HMG-CoA) reductase is the primary target in the current clinical treatment of hypercholesterolemias with specific inhibitors of the "statin" family. Statins are excellent inhibitors of the class I (human) enzyme but relatively poor inhibitors of the class II enzymes of important bacterial pathogens. To investigate the molecular basis for this difference we determined the x-ray structure of the class II Pseudomonas mevalonii HMG-CoA reductase in complex with the statin drug lovastatin. The structure shows lovastatin bound in the active site and its interactions with residues critically involved in catalysis and substrate binding. Binding of lovastatin also displaces the flap domain of the enzyme, which contains the catalytic residue His-381. Comparison with the structures of statins bound to the human enzyme revealed a similar mode of binding but marked differences in specific interactions that account for the observed differences in affinity. We suggest that these differences might be exploited to develop selective class II inhibitors for use as antibacterial agents against pathogenic microorganisms.

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“…This pathway includes condensation of two molecules of acetylCoA to form acetoacetyl-CoA, which is then converted to 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). HMG-CoA in the next step is reduced to MVA, the reaction being catalyzed by HMG-CoA reductase, a key regulatory enzyme of this pathway that has been extensively studied [17]. MVA then undergoes two successive phosphorylation steps to give mevalonic-5-monophosphate (MVA-P) that is converted to mevalonic-5-diphosphate (MVA-PP).…”

Section: Introductionmentioning

confidence: 99%

Targeting the Methyl Erythritol Phosphate (MEP) Pathway for Novel Antimalarial, Antibacterial and Herbicidal Drug Discovery: Inhibition of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase (DXR) Enzyme

Singh

Chevé²,

Avery³

et al. 2007

CPD

105

111

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The 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway for isoprenoid biosynthesis has come under increased scrutiny as a target for novel antimalarial, antibacterial and herbicidal agents. 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme of the pathway that catalyzes the rearrangement and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of 1-deoxy-D-xylulose 5-phosphate (DXP) to MEP. The unique properties of DXR make it a remarkable and rational target for drug design. First, it is a vital enzyme for synthesis of isoprenoids in algae, plants, several eubacteria including the pathogenic bacteria like Bacillus anthracis, Helicobacter pylori, Yersinia pestis, Mycobacterium tuberculosis and the malarial parasite, Plasmodium falciparum. Second, there are no functional equivalents to DXR in humans, making it an attractive target for therapeutic intervention. Third, DXR appears to be a valid target and the results from fosmidomycin (1), the only available DXR inhibitor under clinical trials, suggests synergistic effects with the lincosamide antibiotics, lincomycin and clindamycin. Despite drug design efforts in this area, no successful drug specifically designed to inhibit DXR has emerged yet. This review summarizes the recent and promising developments with respect to the current knowledge of the MEP pathway with emphasis on the understanding of the structure and the catalytic mechanism of the DXR enzyme and the global quest for therapeutically useful inhibitors of DXR.

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3-Hydroxy-3-methylglutaryl-CoA Reductase

Cited by 31 publications

References 22 publications

3‐hydroxy‐3‐methyl glutaryl coenzyme A reductase: an essential actor in the biosynthesis of cantharidin in the blister beetle Epicauta chinensisLaporte

3‐hydroxy‐3‐methyl glutaryl coenzyme A reductase: an essential actor in the biosynthesis of cantharidin in the blister beetle Epicauta chinensisLaporte

Crystal Structure of a Statin Bound to a Class II Hydroxymethylglutaryl-CoA Reductase

Targeting the Methyl Erythritol Phosphate (MEP) Pathway for Novel Antimalarial, Antibacterial and Herbicidal Drug Discovery: Inhibition of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase (DXR) Enzyme

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