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

Tabernero, Lydia; Rodwell, Victor W.; Stauffacher, Cynthia V.

doi:10.1074/jbc.m213006200

Cited by 43 publications

(49 citation statements)

References 28 publications

(35 reference statements)

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“…The ternary structures also revealed that Lys267 participates in catalysis and substrate binding, which was subsequently confirmed by mutagenesis and kinetic studies (4,5). The crystal structure of P. mevalonii HMG-CoA reductase has been solved by using a complex with the inhibitor lovastatin (24). Lovastatin binds in the central HMG pocket, accommodating itself in the same position as mevalonate and the HMG portion of HMG-CoA (Fig.…”

Section: P Mevaloniimentioning

confidence: 67%

Class II 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductases

Hedl¹,

Tabernero

Stauffacher

et al. 2004

J Bacteriol

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Section: P Mevaloniimentioning

confidence: 67%

Class II 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductases

Hedl¹,

Tabernero

Stauffacher

et al. 2004

J Bacteriol

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“…1,2 However, the drugs bind with inhibition constants in the micromolar range and therefore less tightly to the HMGRs of pathogenic bacteria. 18,19 This observation is explained in part by protein sequence alignments of the known HMGR enzymes. Two evolutionarily divergent classes of HMGRs that split roughly by eukaryotes (Class I) and prokaryotes (Class II) were discovered.…”

Section: Introductionmentioning

confidence: 99%

The Increasingly Complex Mechanism of HMG-CoA Reductase

2013

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CONSPECTUS The seven decades of research on the mechanism of HMG-CoA Reductase (HMGR) provided a detailed reaction pathway for what is one of the most biomedically important and mechanistically most complex enzymes. HMGR is the target of statins that are prescribed to improve the quality of life of millions of people worldwide and, more recently, has been identified as a target for the development of antimicrobial agents. The impact of advances in diverse research areas, such as molecular biology and computational chemistry, are reflected in the maturation of mechanistic proposals for HMGR. Thus, the development of state-the-art methods in enzyme mechanism research can be traced by following the development of the HMGR mechanism. Similarly, the questions raised about these mechanism proposals reflect the limitations of these methods. The mechanism of HMGR, a four-electron oxidoreductase, has been uncovered to be unique and far more complex than originally thought. The reaction contains multiple chemical steps, coupled to large- scale domain motions of the homodimeric enzyme. The first proposals for the HMGR mechanism were based on kinetic and labeling experiments, drawing analogies to the mechanism of known dehydrogenases. Advances in molecular biology and bioinformatics enabled site-directed mutagenesis experiments and protein sequence analysis which identified catalytically important glutamate, aspartate, and histidine residues that in turn generated new and more complicated mechanistic proposals. With the development of protein crystallography, HMGR crystal structures were solved to reveal the spatial organization of the active site with an unexpected lysine residue lying at its center. The multitude of crystal structures led to more and more complex mechanistic proposals but the inherent limitations of the protein crystallography left a number of questions unresolved. For example, the proposed mechanisms change based on the protonation state of the active site glutamate residue, which cannot be clearly determined from the crystal structures. As computational analysis of large biomolecules become more feasible, application of methods such as hybrid quantum mechanics/molecular mechanics (QM/MM) calculations to the HMGR mechanism have led to the most detailed mechanistic proposal yet. As these methodologies continue to improve, their power to study enzyme mechanism in conjunction with protein crystallography is enormous. Nevertheless, even the most current mechanistic proposal is yet incomplete due to limitations of the current computational methodologies. Thus, HMGR serves as a model for how combination of increasingly sophisticated experimental and computational methods can elucidate very complex enzyme mechanisms.

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“…It interacts with the residues implicated in catalysis and substrate binding. It also displaced the flap domain of the enzyme which contained the catalytic residue His-381 [13,40,41,52]. This binding with statin prevented HMG-CoA reductase from attaining the functional state.…”

Section: Fig (2b)mentioning

confidence: 99%

“…For the HMG-CoA reductase of P. mevalonii, the catalytic domain contains three conserved acidic residues, viz., Glu 52, Glu 83, and Asp 183 [11,12]. Tabernero et al [13] reported the crystal structure of a lovastatin bound to both class I (human) and class II (bacterial) HMG-CoA reductases. This work gives an impetus for the development of selective class II inhibitors for use as antibacterial agents against pathogenic microorganisms.…”

Section: Introductionmentioning

confidence: 99%

Characterization, Modes of Synthesis, and Pleiotropic Effects of Hypocholesterolemic Compounds - A Review

Seenivasan¹,

Panda

Théodore³

2011

TOEIJ

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Studies on the various cholesterol-lowering agents is one of the important areas in clinical research. Identification and characterization of potential molecules from various sources have been carried out in the past and their relationship with the enzymes which are involved in the cholesterol cascade is gaining interest. In this review, we have highlighted various inhibitors involved in the cholesterol cascade as well as cholesterol-lowering agents, viz., tocotrienol, flavonoids, phytosterols, phytostanols, statins, DADS, and synthetic compounds. The mechanism of action and characterization of these hypocholesterolemic compounds are discussed in this communication. Major natural sources as well as synthetic and biological routes of synthesis of these compounds are reviewed in a concise manner. Especially, various HMG-CoA analogues including statins have been reviewed specifically.

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

Cited by 43 publications

References 28 publications

Class II 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductases

Class II 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductases

The Increasingly Complex Mechanism of HMG-CoA Reductase

Characterization, Modes of Synthesis, and Pleiotropic Effects of Hypocholesterolemic Compounds - A Review

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