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Crystal structure of human mARC1 reveals its exceptional position among eukaryotic molybdenum enzymes.

Kubitza C, Bittner F, Ginsel C, Havemeyer A, Clement B, Scheidig AJ
Proc Natl Acad Sci U S A 115 11958-11963 (2018)
Cited: 22 times
EuropePMC logo PMID: 30397129

Abstract

Biotransformation enzymes ensure a viable homeostasis by regulating reversible cycles of oxidative and reductive reactions. The metabolism of nitrogen-containing compounds is of high pharmaceutical and toxicological relevance because N-oxygenated metabolites derived from reactions mediated by cytochrome P450 enzymes or flavin-dependent monooxygenases are in some cases highly toxic or mutagenic. The molybdenum-dependent mitochondrial amidoxime-reducing component (mARC) was found to be an extremely efficient counterpart, which is able to reduce the full range of N-oxygenated compounds and thereby mediates detoxification reactions. However, the 3D structure of this enzyme was unknown. Here we present the high-resolution crystal structure of human mARC. We give detailed insight into the coordination of its molybdenum cofactor (Moco), the catalytic mechanism, and its ability to reduce a wide range of N-oxygenated compounds. The identification of two key residues will allow future discrimination between mARC paralogs and ensure correct annotation. Since our structural findings contradict in silico predictions that are currently made by online databases, we propose domain definitions for members of the superfamily of Moco sulfurase C-terminal (MOSC) domain-containing proteins. Furthermore, we present evidence for an evolutionary role of mARC for the emergence of the xanthine oxidase protein superfamily. We anticipate the hereby presented crystal structure to be a starting point for future descriptions of MOSC proteins, which are currently poorly structurally characterized.

Reviews - 6fw2 mentioned but not cited (1)

  1. The mitochondrial amidoxime reducing component-from prodrug-activation mechanism to drug-metabolizing enzyme and onward to drug target. Struwe MA, Scheidig AJ, Clement B. J Biol Chem 299 105306 (2023)

Articles - 6fw2 mentioned but not cited (3)

  1. Crystal structure of human mARC1 reveals its exceptional position among eukaryotic molybdenum enzymes. Kubitza C, Bittner F, Ginsel C, Havemeyer A, Clement B, Scheidig AJ. Proc Natl Acad Sci U S A 115 11958-11963 (2018)
  2. Design, Screening, and Characterization of Engineered Phage Endolysins with Extracellular Antibacterial Activity against Gram-Negative Bacteria. Sui B, Wang X, Zhao T, Zhen J, Ren H, Liu W, Zhang X, Zhang C. Appl Environ Microbiol 89 e0058123 (2023)
  3. research-article Exploration of Dark Chemical Genomics Space via Portal Learning: Applied to Targeting the Undruggable Genome and COVID-19 Anti-Infective Polypharmacology. Cai T, Xie L, Chen M, Liu Y, He D, Zhang S, Mura C, Bourne P, Xie L. Res Sq rs.3.rs-1109318 (2021)


Reviews citing this publication (7)

  1. Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria. Zhong Q, Kobe B, Kappler U. Front Microbiol 11 615860 (2020)
  2. Evolution, expression, and substrate specificities of aldehyde oxidase enzymes in eukaryotes. Terao M, Garattini E, Romão MJ, Leimkühler S. J Biol Chem 295 5377-5389 (2020)
  3. From the Eukaryotic Molybdenum Cofactor Biosynthesis to the Moonlighting Enzyme mARC. Tejada-Jimenez M, Chamizo-Ampudia A, Calatrava V, Galvan A, Fernandez E, Llamas A. Molecules 23 (2018)
  4. Advancing Our Understanding of Pyranopterin-Dithiolene Contributions to Moco Enzyme Catalysis. Burgmayer SJN, Kirk ML. Molecules 28 7456 (2023)
  5. Does the Micronutrient Molybdenum Have a Role in Gestational Complications and Placental Health? Foteva V, Fisher JJ, Qiao Y, Smith R. Nutrients 15 3348 (2023)
  6. Role of Nitrate Reductase in NO Production in Photosynthetic Eukaryotes. Tejada-Jimenez M, Llamas A, Galván A, Fernández E. Plants (Basel) 8 (2019)
  7. The History of mARC. Clement B, Struwe MA. Molecules 28 4713 (2023)

Articles citing this publication (11)

  1. A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease. Emdin CA, Haas ME, Khera AV, Aragam K, Chaffin M, Klarin D, Hindy G, Jiang L, Wei WQ, Feng Q, Karjalainen J, Havulinna A, Kiiskinen T, Bick A, Ardissino D, Wilson JG, Schunkert H, McPherson R, Watkins H, Elosua R, Bown MJ, Samani NJ, Baber U, Erdmann J, Gupta N, Danesh J, Saleheen D, Chang KM, Vujkovic M, Voight B, Damrauer S, Lynch J, Kaplan D, Serper M, Tsao P, Million Veteran Program, Mercader J, Hanis C, Daly M, Denny J, Gabriel S, Kathiresan S. PLoS Genet 16 e1008629 (2020)
  2. A genome-first approach to mortality and metabolic phenotypes in MTARC1 p.Ala165Thr (rs2642438) heterozygotes and homozygotes. Schneider CV, Schneider KM, Conlon DM, Park J, Vujkovic M, Zandvakili I, Ko YA, Trautwein C, Center R, Carr RM, Strnad P, Thaiss CA, Rader DJ. Med (N Y) 2 851-863.e3 (2021)
  3. Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17-beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms. Hudert CA, Adams LA, Alisi A, Anstee QM, Crudele A, Draijer LG, EU-PNAFLD investigators, Furse S, Hengstler JG, Jenkins B, Karnebeek K, Kelly DA, Koot BG, Koulman A, Meierhofer D, Melton PE, Mori TA, Snowden SG, van Mourik I, Vreugdenhil A, Wiegand S, Mann JP. Hepatol Commun 6 1934-1948 (2022)
  4. Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects. Peretz H, Lagziel A, Bittner F, Kabha M, Shtauber-Naamati M, Zhuravel V, Usher S, Rump S, Wollers S, Bork B, Mandel H, Falik-Zaccai T, Kalfon L, Graessler J, Zeharia A, Heib N, Shalev H, Landau D, Levartovsky D. Biomedicines 9 788 (2021)
  5. Insights into genetic variants associated with NASH-fibrosis from metabolite profiling. Mann JP, Pietzner M, Wittemans LB, Rolfe EL, Kerrison ND, Imamura F, Forouhi NG, Fauman E, Allison ME, Griffin JL, Koulman A, Wareham NJ, Langenberg C. Hum Mol Genet 29 3451-3463 (2020)
  6. Active Site Structures of the Escherichia coli N-Hydroxylaminopurine Resistance Molybdoenzyme YcbX. Yang J, Struwe M, Scheidig A, Mengell J, Clement B, Kirk ML. Inorg Chem 62 5315-5319 (2023)
  7. Hepatocyte mARC1 promotes fatty liver disease. Lewis LC, Chen L, Hameed LS, Kitchen RR, Maroteau C, Nagarajan SR, Norlin J, Daly CE, Szczerbinska I, Hjuler ST, Patel R, Livingstone EJ, Durrant TN, Wondimu E, BasuRay S, Chandran A, Lee WH, Hu S, Gilboa B, Grandi ME, Toledo EM, Erikat AHA, Hodson L, Haynes WG, Pursell NW, Coppieters K, Fleckner J, Howson JMM, Andersen B, Ruby MA. JHEP Rep 5 100693 (2023)
  8. MARC1 p.A165T variant is associated with decreased markers of liver injury and enhanced antioxidant capacity in autoimmune hepatitis. Janik MK, Smyk W, Kruk B, Szczepankiewicz B, Górnicka B, Lebiedzińska-Arciszewska M, Potes Y, Simões ICM, Weber SN, Lammert F, Więckowski MR, Milkiewicz P, Krawczyk M. Sci Rep 11 24407 (2021)
  9. Mitochondrial amidoxime-reducing component 2 (MARC2) has a significant role in N-reductive activity and energy metabolism. Rixen S, Havemeyer A, Tyl-Bielicka A, Pysniak K, Gajewska M, Kulecka M, Ostrowski J, Mikula M, Clement B. J. Biol. Chem. 294 17593-17602 (2019)
  10. RNA Sequencing of Whole Blood Defines the Signature of High Intensity Exercise at Altitude in Elite Speed Skaters. Glotov AS, Zelenkova IE, Vashukova ES, Shuvalova AR, Zolotareva AD, Polev DE, Barbitoff YA, Glotov OS, Sarana AM, Shcherbak SG, Rozina MA, Gogotova VL, Predeus AV. Genes (Basel) 13 574 (2022)
  11. Reduction of Hydrogen Peroxide by Human Mitochondrial Amidoxime Reducing Component Enzymes. Rixen S, Indorf PM, Kubitza C, Struwe MA, Klopp C, Scheidig AJ, Kunze T, Clement B. Molecules 28 6384 (2023)


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