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Crystal structure of 2-enoyl-CoA hydratase 2 from human peroxisomal multifunctional enzyme type 2.

Koski KM, Haapalainen AM, Hiltunen JK, Glumoff T
J Mol Biol 345 1157-69 (2005)
Cited: 38 times
EuropePMC logo PMID: 15644212

Abstract

2-Enoyl-CoA hydratase 2 is the middle part of the mammalian peroxisomal multifunctional enzyme type 2 (MFE-2), which is known to be important in the beta-oxidation of very-long-chain and alpha-methyl-branched fatty acids as well as in the synthesis of bile acids. Here, we present the crystal structure of the hydratase 2 from the human MFE-2 to 3A resolution. The three-dimensional structure resembles the recently solved crystal structure of hydratase 2 from the yeast, Candida tropicalis, MFE-2 having a two-domain subunit structure with a C-domain complete hot-dog fold housing the active site, and an N-domain incomplete hot-dog fold housing the cavity for the aliphatic acyl part of the substrate molecule. The ability of human hydratase 2 to utilize such bulky compounds which are not physiological substrates for the fungal ortholog, e.g. CoA esters of C26 fatty acids, pristanic acid and di/trihydroxycholestanoic acids, is explained by a large hydrophobic cavity formed upon the movements of the extremely mobile loops I-III in the N-domain. In the unliganded form of human hydratase 2, however, the loop I blocks the entrance of fatty enoyl-CoAs with chain-length >C8. Therefore, we expect that upon binding of substrates bulkier than C8, the loop I gives way, contemporaneously causing a secondary effect in the CoA-binding pocket and/or active site required for efficient hydration reaction. This structural feature would explain the inactivity of human hydratase 2 towards short-chain substrates. The solved structure is also used as a tool for analyzing the various inactivating mutations, identified among others in MFE-2-deficient patients. Since hydratase 2 is the last functional unit of mammalian MFE-2 whose structure has been solved, the organization of the functional units in the biologically active full-length enzyme is also discussed.

Reviews - 1s9c mentioned but not cited (1)

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Articles - 1s9c mentioned but not cited (10)

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  6. 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)
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Reviews citing this publication (8)

  1. Peroxisomal beta-oxidation--a metabolic pathway with multiple functions. Poirier Y, Antonenkov VD, Glumoff T, Hiltunen JK. Biochim Biophys Acta 1763 1413-1426 (2006)
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  3. New insights into the formation of fungal aromatic polyketides. Crawford JM, Townsend CA. Nat Rev Microbiol 8 879-889 (2010)
  4. Pathogen roid rage: cholesterol utilization by Mycobacterium tuberculosis. Wipperman MF, Sampson NS, Thomas ST. Crit Rev Biochem Mol Biol 49 269-293 (2014)
  5. Structure and function of eukaryotic fatty acid synthases. Maier T, Leibundgut M, Boehringer D, Ban N. Q Rev Biophys 43 373-422 (2010)
  6. Peroxisomal multifunctional protein-2: the enzyme, the patients and the knockout mouse model. Huyghe S, Mannaerts GP, Baes M, Van Veldhoven PP. Biochim Biophys Acta 1761 973-994 (2006)
  7. Structural biology of the thioester-dependent degradation and synthesis of fatty acids. Bhaumik P, Koski MK, Glumoff T, Hiltunen JK, Wierenga RK. Curr Opin Struct Biol 15 621-628 (2005)
  8. Stereochemistry of enzymatic water addition to C=C bonds. Chen BS, Otten LG, Hanefeld U. Biotechnol Adv 33 526-546 (2015)

Articles citing this publication (19)

  1. Crystal structure of the erythromycin polyketide synthase dehydratase. Keatinge-Clay A. J Mol Biol 384 941-953 (2008)
  2. Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization. Crawford JM, Korman TP, Labonte JW, Vagstad AL, Hill EA, Kamari-Bidkorpeh O, Tsai SC, Townsend CA. Nature 461 1139-1143 (2009)
  3. Binding specificity of Toll-like receptor cytoplasmic domains. Brown V, Brown RA, Ozinsky A, Hesselberth JR, Fields S. Eur J Immunol 36 742-753 (2006)
  4. Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent. Halloum I, Carrère-Kremer S, Blaise M, Viljoen A, Bernut A, Le Moigne V, Vilchèze C, Guérardel Y, Lutfalla G, Herrmann JL, Jacobs WR, Kremer L. Proc Natl Acad Sci U S A 113 E4228-37 (2016)
  5. The selective addition of water to C=C bonds; enzymes are the best chemists. Jin J, Hanefeld U. Chem Commun (Camb) 47 2502-2510 (2011)
  6. 17beta-hydroxysteroid dehydrogenase type 8 and carbonyl reductase type 4 assemble as a ketoacyl reductase of human mitochondrial FAS. Chen Z, Kastaniotis AJ, Miinalainen IJ, Rajaram V, Wierenga RK, Hiltunen JK. FASEB J 23 3682-3691 (2009)
  7. Peroxisomal multifunctional enzyme type 2 from the fruitfly: dehydrogenase and hydratase act as separate entities, as revealed by structure and kinetics. Haataja TJ, Koski MK, Hiltunen JK, Glumoff T. Biochem J 435 771-781 (2011)
  8. A new dehydratase conferring innate resistance to thiacetazone and intra-amoebal survival of Mycobacterium smegmatis. Carrère-Kremer S, Blaise M, Singh VK, Alibaud L, Tuaillon E, Halloum I, van de Weerd R, Guérardel Y, Drancourt M, Takiff H, Geurtsen J, Kremer L. Mol Microbiol 96 1085-1102 (2015)
  9. Molecular basis for the inhibition of β-hydroxyacyl-ACP dehydratase HadAB complex from Mycobacterium tuberculosis by flavonoid inhibitors. Dong Y, Qiu X, Shaw N, Xu Y, Sun Y, Li X, Li J, Rao Z. Protein Cell 6 504-517 (2015)
  10. Crystal structure of yeast peroxisomal multifunctional enzyme: structural basis for substrate specificity of (3R)-hydroxyacyl-CoA dehydrogenase units. Ylianttila MS, Pursiainen NV, Haapalainen AM, Juffer AH, Poirier Y, Hiltunen JK, Glumoff T. J Mol Biol 358 1286-1295 (2006)
  11. An additional dehydratase-like activity is required for lankacidin antibiotic biosynthesis. Dickschat JS, Vergnolle O, Hong H, Garner S, Bidgood SR, Dooley HC, Deng Z, Leadlay PF, Sun Y. Chembiochem 12 2408-2412 (2011)
  12. Human Δ³,Δ²-enoyl-CoA isomerase, type 2: a structural enzymology study on the catalytic role of its ACBP domain and helix-10. Onwukwe GU, Kursula P, Koski MK, Schmitz W, Wierenga RK. FEBS J 282 746-768 (2015)
  13. Species used for drug testing reveal different inhibition susceptibility for 17beta-hydroxysteroid dehydrogenase type 1. Möller G, Husen B, Kowalik D, Hirvelä L, Plewczynski D, Rychlewski L, Messinger J, Thole H, Adamski J. PLoS One 5 e10969 (2010)
  14. On the molecular basis of D-bifunctional protein deficiency type III. Mehtälä ML, Lensink MF, Pietikäinen LP, Hiltunen JK, Glumoff T. PLoS One 8 e53688 (2013)
  15. Peroxisomal D-bifunctional protein deficiency: First case reports from Slovakia. Konkoľová J, Petrovič R, Chandoga J, Repiský M, Zelinková H, Kršiaková J, Kolníková M, Kantarská D, Šutovský S, Böhmer D. Gene 568 61-68 (2015)
  16. Quaternary structure of human, Drosophila melanogaster and Caenorhabditis elegans MFE-2 in solution from synchrotron small-angle X-ray scattering. Mehtälä ML, Haataja TJ, Blanchet CE, Hiltunen JK, Svergun DI, Glumoff T. FEBS Lett 587 305-310 (2013)
  17. Contribution of the distal pocket residue to the acyl-chain-length specificity of (R)-specific enoyl-coenzyme A hydratases from Pseudomonas spp. Tsuge T, Sato S, Hiroe A, Ishizuka K, Kanazawa H, Shiro Y, Hisano T. Appl Environ Microbiol 81 8076-8083 (2015)
  18. Structural characterization of HypX responsible for CO biosynthesis in the maturation of NiFe-hydrogenase. Muraki N, Ishii K, Uchiyama S, Itoh SG, Okumura H, Aono S. Commun Biol 2 385 (2019)
  19. Bacterial Hydratases Involved in Steroid Side Chain Degradation Have Distinct Substrate Specificities. Schroeter KL, Abraham N, Rolfe N, Barnshaw R, Diamond J, Seah SYK. J Bacteriol 204 e0023622 (2022)


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