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Crystal structures of malonyl-coenzyme A decarboxylase provide insights into its catalytic mechanism and disease-causing mutations.

<div class='caption-title'>Sequence Alignment of HsMCD, RpMCD, CmMCD, AvMCD, and ReMCD</div>
<div class='caption-title'>Crystal Structures of MCD Monomer</div>
<div class='caption-title'>The Oligomers of MCD</div>
Froese DS, Forouhar F, Tran TH, Vollmar M, Kim YS, Lew S, Neely H, Seetharaman J, Shen Y, Xiao R, Acton TB, Everett JK, Cannone G, Puranik S, Savitsky P, Krojer T, Pilka ES, Kiyani W, Lee WH, Marsden BD, von Delft F, Allerston CK, Spagnolo L, Gileadi O, Montelione GT, Oppermann U, Yue WW, Tong L
OpenAccess logo Structure 21 1182-92 (2013)
Related entries: 4ks9, 4ksa, 4ksf

Cited: 16 times
EuropePMC logo PMID: 23791943

Abstract

Malonyl-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.

Reviews - 2ygw mentioned but not cited (1)

  1. From structural biology to designing therapy for inborn errors of metabolism. Yue WW. J Inherit Metab Dis 39 489-498 (2016)

Articles - 2ygw mentioned but not cited (4)

  1. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, Dephoure N, Fischer F, Boanca G, Vaitheesvaran B, Lovitch SB, Sharpe AH, Kurland IJ, Steegborn C, Gygi SP, Muoio DM, Ruderman NB, Haigis MC. Mol Cell 50 686-698 (2013)
  2. Repurposing the GNAT Fold in the Initiation of Polyketide Biosynthesis. Skiba MA, Tran CL, Dan Q, Sikkema AP, Klaver Z, Gerwick WH, Sherman DH, Smith JL. Structure 28 63-74.e4 (2020)
  3. Structural asymmetry and disulfide bridges among subunits modulate the activity of human malonyl-CoA decarboxylase. Aparicio D, Pérez-Luque R, Carpena X, Díaz M, Ferrer JC, Loewen PC, Fita I. J Biol Chem 288 11907-11919 (2013)
  4. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)


Articles citing this publication (11)

  1. Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project. Roman TS, Crowley SB, Roche MI, Foreman AKM, O'Daniel JM, Seifert BA, Lee K, Brandt A, Gustafson C, DeCristo DM, Strande NT, Ramkissoon L, Milko LV, Owen P, Roy S, Xiong M, Paquin RS, Butterfield RM, Lewis MA, Souris KJ, Bailey DB, Rini C, Booker JK, Powell BC, Weck KE, Powell CM, Berg JS. Am J Hum Genet 107 596-611 (2020)
  2. A Mononuclear Iron-Dependent Methyltransferase Catalyzes Initial Steps in Assembly of the Apratoxin A Polyketide Starter Unit. Skiba MA, Sikkema AP, Moss NA, Tran CL, Sturgis RM, Gerwick L, Gerwick WH, Sherman DH, Smith JL. ACS Chem Biol 12 3039-3048 (2017)
  3. Biosynthesis of t-Butyl in Apratoxin A: Functional Analysis and Architecture of a PKS Loading Module. Skiba MA, Sikkema AP, Moss NA, Lowell AN, Su M, Sturgis RM, Gerwick L, Gerwick WH, Sherman DH, Smith JL. ACS Chem Biol 13 1640-1650 (2018)
  4. Malonyl-CoA decarboxylase deficiency: long-term follow-up of a patient new clinical features and novel mutations. Polinati PP, Valanne L, Tyni T. Brain Dev 37 107-113 (2015)
  5. A Single Amino Acid Mutation Converts (R)-5-Diphosphomevalonate Decarboxylase into a Kinase. Motoyama K, Unno H, Hattori A, Takaoka T, Ishikita H, Kawaide H, Yoshimura T, Hemmi H. J Biol Chem 292 2457-2469 (2017)
  6. Crystal structure of a Pseudomonas malonate decarboxylase holoenzyme hetero-tetramer. Maderbocus R, Fields BL, Hamilton K, Luo S, Tran TH, Dietrich LEP, Tong L. Nat Commun 8 160 (2017)
  7. A new case of malonyl-CoA decarboxylase deficiency with mild clinical features. Liu H, Tan D, Han L, Ye J, Qiu W, Gu X, Zhang H. Am J Med Genet A 170A 1347-1351 (2016)
  8. The SCP2-thiolase-like protein (SLP) of Trypanosoma brucei is an enzyme involved in lipid metabolism. Harijan RK, Mazet M, Kiema TR, Bouyssou G, Alexson SE, Bergmann U, Moreau P, Michels PA, Bringaud F, Wierenga RK. Proteins 84 1075-1096 (2016)
  9. Case Reports Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family. Snanoudj S, Torre S, Sudrié-Arnaud B, Abily-Donval L, Goldenberg A, Salomons GS, Marret S, Bekri S, Tebani A. Int J Mol Sci 22 12633 (2021)
  10. Phosphorylation of Ser-204 and Tyr-405 in human malonyl-CoA decarboxylase expressed in silkworm Bombyx mori regulates catalytic decarboxylase activity. Hwang IW, Makishima Y, Suzuki T, Kato T, Park S, Terzic A, Chung SK, Park EY. Appl Microbiol Biotechnol 99 8977-8986 (2015)
  11. Identification of the active site of human mitochondrial malonyl-coenzyme a decarboxylase: A combined computational study. Ling B, Liu Y, Li X, Wang Z, Bi S. Proteins 84 792-802 (2016)


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