Structural Asymmetry and Disulfide Bridges among Subunits Modulate the Activity of Human Malonyl-CoA Decarboxylase

Aparicio, David; Pérez-Luque, R.; Carpena, X.; Díaz, Mireia; Ferrer, Juan C.; Loewen, P.C.; Fita, Ignacio

doi:10.1074/jbc.m112.443846

Cited by 10 publications

(19 citation statements)

References 25 publications

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“…While this paper was under review, a structure of HsMCD at 3.29 Å resolution was reported (Aparicio et al., 2013). The overall structures of the HsMCD monomers in the two reports are similar, with rms distance of 1.5 Å for 380 equivalent Cα atoms (Figure S2).…”

Section: Resultsmentioning

confidence: 99%

Crystal Structures of Malonyl-Coenzyme A Decarboxylase Provide Insights into Its Catalytic Mechanism and Disease-Causing Mutations

et al. 2013

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SummaryMalonyl-coenzyme A decarboxylase (MCD) is found from bacteria to humans, has important roles in regulating fatty acid metabolism and food intake, and is an attractive target for drug discovery. We report here four crystal structures of MCD from human, Rhodopseudomonas palustris, Agrobacterium vitis, and Cupriavidus metallidurans at up to 2.3 Å resolution. The MCD monomer contains an N-terminal helical domain involved in oligomerization and a C-terminal catalytic domain. The four structures exhibit substantial differences in the organization of the helical domains and, consequently, the oligomeric states and intersubunit interfaces. Unexpectedly, the MCD catalytic domain is structurally homologous to those of the GCN5-related N-acetyltransferase superfamily, especially the curacin A polyketide synthase catalytic module, with a conserved His-Ser/Thr dyad important for catalysis. Our structures, along with mutagenesis and kinetic studies, provide a molecular basis for understanding pathogenic mutations and catalysis, as well as a template for structure-based drug design.

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Section: Resultsmentioning

confidence: 99%

Crystal Structures of Malonyl-Coenzyme A Decarboxylase Provide Insights into Its Catalytic Mechanism and Disease-Causing Mutations

et al. 2013

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“…The monomer of MCD has an N-terminal helical domain for oligomerization and a C-terminal domain for catalysis, and the active site of MCD is located in a prominent groove clustered with evolutionarily conserved residues (Fig. 5a) (Aparicio et al 2013;Froese et al 2013). Through inter-subunit disulfide bonds, Cys-206-Cys-206 and Cys-243-Cys-243 (Fig.…”

Section: Structural Implication Of Hmcd Phosphorylationmentioning

confidence: 98%

“…Through inter-subunit disulfide bonds, Cys-206-Cys-206 and Cys-243-Cys-243 (Fig. 5b), the four subunits of the tetramer are connected, providing positive cooperativity to the decarboxylase catalytic function (Aparicio et al 2013).…”

Section: Structural Implication Of Hmcd Phosphorylationmentioning

confidence: 99%

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Phosphorylation of Ser-204 and Tyr-405 in human malonyl-CoA decarboxylase expressed in silkworm Bombyx mori regulates catalytic decarboxylase activity

Hwang

Makishima

Suzuki

et al. 2015

Appl Microbiol Biotechnol

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Decarboxylation of malonyl-CoA to acetyl-CoA by malonyl-CoA decarboxylase (MCD; EC 4.1.1.9) is a vital catalytic reaction of lipid metabolism. While it is established that phosphorylation of MCD modulates the enzymatic activity, the specific phosphorylation sites associated with the catalytic function have not been documented due to lack of sufficient production of MCD with proper post-translational modifications. Here, we used the silkworm-based Bombyx mori nucleopolyhedrovirus (BmNPV) bacmid system to express human MCD (hMCD) and mapped phosphorylation effects on enzymatic function. Purified MCD from silkworm displayed post-translational phosphorylation and demonstrated coherent enzymatic activity with high yield (-200 μg/silkworm). Point mutations in putative phosphorylation sites, Ser-204 or Tyr-405 of hMCD, identified by bioinformatics and proteomics analyses reduced the catalytic activity, underscoring the functional significance of phosphorylation in modulating decarboxylase-based catalysis. Identified phosphorylated residues are distinct from the decarboxylation catalytic site, implicating a phosphorylation-induced global conformational change of MCD as responsible in altering catalytic function. We conclude that phosphorylation of Ser-204 and Tyr-405 regulates the decarboxylase function of hMCD leveraging the silkworm-based BmNPV bacmid expression system that offers a fail-safe eukaryotic production platform implementing proper post-translational modification such as phosphorylation.

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“…The available crystal structures from human mitochondrial and peroxisomal MCDs have been reported by Froese et al . and Aparicio et al . in 2013, respectively.…”

Section: Introductionmentioning

confidence: 99%

Identification of the active site of human mitochondrial malonyl‐coenzyme a decarboxylase: A combined computational study

Ling

Liu

et al. 2016

Proteins

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Malonyl-CoA decarboxylase (MCD) can control the level of malonyl-CoA in cell through the decarboxylation of malonyl-CoA to acetyl-CoA, and plays an essential role in regulating fatty acid metabolism, thus it is a potential target for drug discovery. However, the interactions of MCD with CoA derivatives are not well understood owing to unavailable crystal structure with a complete occupancy in the active site. To identify the active site of MCD, molecular docking and molecular dynamics simulations were performed to explore the interactions of human mitochondrial MCD (HmMCD) and CoA derivatives. The findings reveal that the active site of HmMCD indeed resides in the prominent groove which resembles that of CurA. However, the binding modes are slightly different from the one observed in CurA due to the occupancy of the side chain of Lys183 from the N-terminal helical domain instead of the adenine ring of CoA. The residues 300 - 305 play an essential role in maintaining the stability of complex mainly through hydrogen bond interactions with the pyrophosphate moiety of acetyl-CoA. Principle component analysis elucidates the conformational distribution and dominant concerted motions of HmMCD. MM_PBSA calculations present the crucial residues and the major driving force responsible for the binding of acetyl-CoA. These results provide useful information for understanding the interactions of HmMCD with CoA derivatives. Proteins 2016; 84:792-802. © 2016 Wiley Periodicals, Inc.

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Structural Asymmetry and Disulfide Bridges among Subunits Modulate the Activity of Human Malonyl-CoA Decarboxylase

Cited by 10 publications

References 25 publications

Crystal Structures of Malonyl-Coenzyme A Decarboxylase Provide Insights into Its Catalytic Mechanism and Disease-Causing Mutations

Crystal Structures of Malonyl-Coenzyme A Decarboxylase Provide Insights into Its Catalytic Mechanism and Disease-Causing Mutations

Phosphorylation of Ser-204 and Tyr-405 in human malonyl-CoA decarboxylase expressed in silkworm Bombyx mori regulates catalytic decarboxylase activity

Identification of the active site of human mitochondrial malonyl‐coenzyme a decarboxylase: A combined computational study

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