Human mevalonate diphosphate decarboxylase: Characterization, investigation of the mevalonate diphosphate binding site, and crystal structure

Voynova, Natalia E.; Fu, Zuoling; Battaile, Kevin P.; Herdendorf, Timothy J.; Kim, Jung‐Ja P.; Miziorko, Henry M.

doi:10.1016/j.abb.2008.08.024

Cited by 40 publications

(57 citation statements)

References 36 publications

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“…Following modeling and refinement of two copies of MDD, analysis of an F o Ϫ F c difference map revealed a region of strong contiguous density within the MDD active site cleft (Fig. 3A) (11). Placement and refinement of a single (R)-DPGP molecule per enzyme monomer (occupancy of 0.80 and 0.92 in chain A and B, respectively) are in good agreement with the observed diffraction data (Table 2 and Fig.…”

Section: Kinetic Characterization and Crystal Structure Of Mdd Fromsupporting

confidence: 73%

“…Preparation of FMVAPP employed the method described by Voynova et al (11). Five milligrams (33.8 mol) of (RS)-6-fluoromevalonolactone was delactonized in 0.1 N KOH by incubation for 1 h at 37°C prior to neutralization.…”

Section: Methodsmentioning

confidence: 99%

“…Previous investigation into the MDD mechanism has identified two separate diphosphorylated compounds, DPGP (11) and FMVAPP (16,39), that mimic the MVAPP substrate and competitively inhibit MDD activity (11). Despite these similarities, characterization of their effects on S. epidermidis MDD a Numbers in parentheses are for the highest resolution shell.…”

Section: Kinetic Characterization and Crystal Structure Of Mdd Frommentioning

confidence: 99%

“…These enzymes are characterized by a cone-shaped fold, where the ␤-grasp-like N-terminal region packs orthogonally against the relatively planar C-terminal region comprised of five prominent ␣-helices (13). High resolution crystal structures of MDD proteins have been reported from a number of species across several kingdoms of life, including S. aureus (13), Trypanosoma brucei (13), Saccharomyces cerevisiae (12), as well as Homo sapiens (11). These structures reveal the presence of a deep cleft that forms between the roughly equal halves of the enzyme, which houses the catalytic Asp and Arg residues.…”

mentioning

confidence: 99%

“…It is this, in conjunction with interactions between the C1 carboxylate and the guanidinium group Arg 144 , that drives subsequent decarboxylation and production of IPP. Indeed, mutation of either of these side chains results in a 3-5 order of magnitude decrease in catalysis (7,11).…”

mentioning

confidence: 99%

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Crystal Structures of Staphylococcus epidermidis Mevalonate Diphosphate Decarboxylase Bound to Inhibitory Analogs Reveal New Insight into Substrate Binding and Catalysis

Barta

Skaff

McWhorter

et al. 2011

Journal of Biological Chemistry

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The polyisoprenoid compound undecaprenyl phosphate is required for biosynthesis of cell wall peptidoglycans in Grampositive bacteria, including pathogenic Enterococcus, Streptococcus, and Staphylococcus spp. In these organisms, the mevalonate pathway is used to produce the precursor isoprenoid, isopentenyl 5-diphosphate. Mevalonate diphosphate decarboxylase (MDD) catalyzes formation of isopentenyl 5-diphosphate in an ATP-dependent irreversible reaction and is therefore an attractive target for inhibitor development that could lead to new antimicrobial agents. To facilitate exploration of this possibility, we report the crystal structure of Staphylococcus epidermidis MDD (1.85 Å resolution) and, to the best of our knowledge, the first structures of liganded MDD. These structures include MDD bound to the mevalonate 5-diphosphate analogs diphosphoglycolyl proline (2.05 Å resolution) and 6-fluoromevalonate diphosphate (FMVAPP; 2.2 Å resolution). Comparison of these structures provides a physical basis for the significant differences in K i values observed for these inhibitors. Inspection of enzyme/ inhibitor structures identified the side chain of invariant Ser 192 as making potential contributions to catalysis. Significantly, Ser 3 Ala substitution of this side chain decreases k cat by ϳ10 3 -fold, even though binding interactions between FMVAPP and this mutant are similar to those observed with wild type MDD, as judged by the 2.1 Å cocrystal structure of S192A with FMVAPP. Comparison of microbial MDD structures with those of mammalian counterparts reveals potential targets at the active site periphery that may be exploited to selectively target the microbial enzymes. These studies provide a structural basis for previous observations regarding the MDD mechanism and inform future work toward rational inhibitor design.The ever-growing trend among many bacterial pathogens toward antibiotic resistance represents one of the single greatest threats to public health in both developing and modern nations. In particular, a growing body of literature from the last decade has demonstrated that many strains of the widespread Gram-positive organisms Staphylococcus aureus and Staphylococcus epidermidis are now insensitive toward an array of the ␤-lactam class antibiotics that were once considered frontline therapeutics (1, 2). As recently as a few years ago, the problem of antibiotic resistance was associated primarily with those infections arising from within the healthcare setting. However, recent studies have shown that resistant strains are now spreading rapidly within the community, where they may cause potentially life-threatening illness in persons not recently hospitalized or undergoing invasive medical procedures (1, 3). Given the limited nature of effective therapeutic tools to combat these diseases, all such infections must be carefully managed to prevent further spread throughout the population. As a consequence, there is now renewed interest in novel classes of antimicrobials that are effective against sensitive and...

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Section: Kinetic Characterization and Crystal Structure Of Mdd Fromsupporting

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Kinetic Characterization and Crystal Structure Of Mdd Frommentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Crystal Structures of Staphylococcus epidermidis Mevalonate Diphosphate Decarboxylase Bound to Inhibitory Analogs Reveal New Insight into Substrate Binding and Catalysis

Barta

Skaff

McWhorter

et al. 2011

Journal of Biological Chemistry

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Phosphomevalonate Kinase Controls β‐Catenin Signaling via the Metabolite 5‐Diphosphomevalonate

Chen

Zhou

et al. 2023

Advanced Science

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β‐catenin signaling is abnormally activated in cancer. Here, this work screens the mevalonate metabolic pathway enzyme PMVK to stabilize β‐catenin signaling using a human genome‐wide library. On the one hand, PMVK‐produced MVA‐5PP competitively binds to CKIα to prevent β‐catenin Ser45 phosphorylation and degradation. On the other hand, PMVK functions as a protein kinase to directly phosphorylate β‐catenin Ser184 to increase its protein nuclear localization. This synergistic effect of PMVK and MVA‐5PP together promotes β‐catenin signaling. In addition, PMVK deletion impairs mouse embryonic development and causes embryonic lethal. PMVK deficiency in liver tissue alleviates DEN/CCl4‐induced hepatocarcinogenesis. Finally, the small molecule inhibitor of PMVK, PMVKi5, is developed and PMVKi5 inhibits carcinogenesis of liver and colorectal tissues. These findings reveal a non‐canonical function of a key metabolic enzyme PMVK and a novel link between the mevalonate pathway and β‐catenin signaling in carcinogenesis providing a new target for clinical cancer therapy.

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New candidate loci identified by array‐CGH in a cohort of 100 children presenting with syndromic obesity

Vuillaume

Naudion

Banneau³

et al. 2014

American J of Med Genetics Pt A

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Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray-based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6).

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Human mevalonate diphosphate decarboxylase: Characterization, investigation of the mevalonate diphosphate binding site, and crystal structure

Cited by 40 publications

References 36 publications

Crystal Structures of Staphylococcus epidermidis Mevalonate Diphosphate Decarboxylase Bound to Inhibitory Analogs Reveal New Insight into Substrate Binding and Catalysis

Crystal Structures of Staphylococcus epidermidis Mevalonate Diphosphate Decarboxylase Bound to Inhibitory Analogs Reveal New Insight into Substrate Binding and Catalysis

Phosphomevalonate Kinase Controls β‐Catenin Signaling via the Metabolite 5‐Diphosphomevalonate

New candidate loci identified by array‐CGH in a cohort of 100 children presenting with syndromic obesity

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