3utf › Citations

Crystal structures and small-angle x-ray scattering analysis of UDP-galactopyranose mutase from the pathogenic fungus Aspergillus fumigatus.

Dhatwalia R, Singh H, Oppenheimer M, Karr DB, Nix JC, Sobrado P, Tanner JJ
J Biol Chem 287 9041-51 (2012)
Related entries: 3ute, 3utg, 3uth

Cited: 27 times
EuropePMC logo PMID: 22294687

Abstract

UDP-galactopyranose mutase (UGM) is a flavoenzyme that catalyzes the conversion of UDP-galactopyranose to UDP-galactofuranose, which is a central reaction in galactofuranose biosynthesis. Galactofuranose has never been found in humans but is an essential building block of the cell wall and extracellular matrix of many bacteria, fungi, and protozoa. The importance of UGM for the viability of many pathogens and its absence in humans make UGM a potential drug target. Here we report the first crystal structures and small-angle x-ray scattering data for UGM from the fungus Aspergillus fumigatus, the causative agent of aspergillosis. The structures reveal that Aspergillus UGM has several extra secondary and tertiary structural elements that are not found in bacterial UGMs yet are important for substrate recognition and oligomerization. Small-angle x-ray scattering data show that Aspergillus UGM forms a tetramer in solution, which is unprecedented for UGMs. The binding of UDP or the substrate induces profound conformational changes in the enzyme. Two loops on opposite sides of the active site move toward each other by over 10 Å to cover the substrate and create a closed active site. The degree of substrate-induced conformational change exceeds that of bacterial UGMs and is a direct consequence of the unique quaternary structure of Aspergillus UGM. Galactopyranose binds at the re face of the FAD isoalloxazine with the anomeric carbon atom poised for nucleophilic attack by the FAD N5 atom. The structural data provide new insight into substrate recognition and the catalytic mechanism and thus will aid inhibitor design.

Reviews - 3utf mentioned but not cited (2)

  1. Structure, mechanism, and dynamics of UDP-galactopyranose mutase. Tanner JJ, Boechi L, Andrew McCammon J, Sobrado P. Arch Biochem Biophys 544 128-141 (2014)
  2. Targeting UDP-galactopyranose mutases from eukaryotic human pathogens. Kizjakina K, Tanner JJ, Sobrado P. Curr Pharm Des 19 2561-2573 (2013)

Articles - 3utf mentioned but not cited (5)

  1. Crystal structures and small-angle x-ray scattering analysis of UDP-galactopyranose mutase from the pathogenic fungus Aspergillus fumigatus. Dhatwalia R, Singh H, Oppenheimer M, Karr DB, Nix JC, Sobrado P, Tanner JJ. J Biol Chem 287 9041-9051 (2012)
  2. Identification of the NAD(P)H binding site of eukaryotic UDP-galactopyranose mutase. Dhatwalia R, Singh H, Solano LM, Oppenheimer M, Robinson RM, Ellerbrock JF, Sobrado P, Tanner JJ. J Am Chem Soc 134 18132-18138 (2012)
  3. Substrate-dependent dynamics of UDP-galactopyranose mutase: Implications for drug design. Boechi L, de Oliveira CA, Da Fonseca I, Kizjakina K, Sobrado P, Tanner JJ, McCammon JA. Protein Sci 22 1490-1501 (2013)
  4. Contributions of unique active site residues of eukaryotic UDP-galactopyranose mutases to substrate recognition and active site dynamics. Da Fonseca I, Qureshi IA, Mehra-Chaudhary R, Kizjakina K, Tanner JJ, Sobrado P. Biochemistry 53 7794-7804 (2014)
  5. Identification of eukaryotic UDP-galactopyranose mutase inhibitors using the ThermoFAD assay. Martín Del Campo JS, Eckshtain-Levi M, Sobrado P. Biochem Biophys Res Commun 493 58-63 (2017)


Reviews citing this publication (5)

  1. Determination of protein oligomeric structure from small-angle X-ray scattering. Korasick DA, Tanner JJ. Protein Sci 27 814-824 (2018)
  2. Noncanonical reactions of flavoenzymes. Sobrado P. Int J Mol Sci 13 14219-14242 (2012)
  3. Modeling and Structure Determination of Homo-Oligomeric Proteins: An Overview of Challenges and Current Approaches. Gaber A, Pavšič M. Int J Mol Sci 22 9081 (2021)
  4. Multiple functionalities of reduced flavin in the non-redox reaction catalyzed by UDP-galactopyranose mutase. Sobrado P, Tanner JJ. Arch Biochem Biophys 632 59-65 (2017)
  5. N5 Is the New C4a: Biochemical Functionalization of Reduced Flavins at the N5 Position. Beaupre BA, Moran GR. Front Mol Biosci 7 598912 (2020)

Articles citing this publication (15)

  1. Crystal structures of Trypanosoma cruzi UDP-galactopyranose mutase implicate flexibility of the histidine loop in enzyme activation. Dhatwalia R, Singh H, Oppenheimer M, Sobrado P, Tanner JJ. Biochemistry 51 4968-4979 (2012)
  2. Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents. Kincaid VA, London N, Wangkanont K, Wesener DA, Marcus SA, Héroux A, Nedyalkova L, Talaat AM, Forest KT, Shoichet BK, Kiessling LL. ACS Chem Biol 10 2209-2218 (2015)
  3. In Crystallo Capture of a Covalent Intermediate in the UDP-Galactopyranose Mutase Reaction. Mehra-Chaudhary R, Dai Y, Sobrado P, Tanner JJ. Biochemistry 55 833-836 (2016)
  4. Reversible and efficient inhibition of UDP-galactopyranose mutase by electrophilic, constrained and unsaturated UDP-galactitol analogues. Ansiaux C, N'Go I, Vincent SP. Chemistry 18 14860-14866 (2012)
  5. UDP-galactopyranose mutase in nematodes. Wesener DA, May JF, Huffman EM, Kiessling LL. Biochemistry 52 4391-4398 (2013)
  6. Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors. Villaume SA, Fu J, N'Go I, Liang H, Lou H, Kremer L, Pan W, Vincent SP. Chemistry 23 10423-10429 (2017)
  7. Empirical power laws for the radii of gyration of protein oligomers. Tanner JJ. Acta Crystallogr D Struct Biol 72 1119-1129 (2016)
  8. QM/MM molecular dynamics study of the galactopyranose → galactofuranose reaction catalysed by Trypanosoma cruzi UDP-galactopyranose mutase. Pierdominici-Sottile G, Cossio Pérez R, Galindo JF, Palma J. PLoS One 9 e109559 (2014)
  9. A covalent adduct of MbtN, an acyl-ACP dehydrogenase from Mycobacterium tuberculosis, reveals an unusual acyl-binding pocket. Chai AF, Bulloch EM, Evans GL, Lott JS, Baker EN, Johnston JM. Acta Crystallogr D Biol Crystallogr 71 862-872 (2015)
  10. UDP-galactopyranose mutases from Leishmania species that cause visceral and cutaneous leishmaniasis. Fonseca IO, Kizjakina K, Sobrado P. Arch Biochem Biophys 538 103-110 (2013)
  11. Structure and function of a flavin-dependent S-monooxygenase from garlic (Allium sativum). Valentino H, Campbell AC, Schuermann JP, Sultana N, Nam HG, LeBlanc S, Tanner JJ, Sobrado P. J Biol Chem 295 11042-11055 (2020)
  12. UDP-galactopyranose mutase, a potential drug target against human pathogenic nematode Brugia malayi. Misra S, Valicherla GR, Mohd Shahab, Gupta J, Gayen JR, Misra-Bhattacharya S. Pathog Dis 74 ftw072 (2016)
  13. Conformational Control of UDP-Galactopyranose Mutase Inhibition. Wangkanont K, Winton VJ, Forest KT, Kiessling LL. Biochemistry 56 3983-3992 (2017)
  14. Molecular Dynamics Simulations of Substrate Release from Trypanosoma cruzi UDP-Galactopyranose Mutase. Cossio-Pérez R, Pierdominici-Sottile G, Sobrado P, Palma J. J Chem Inf Model 59 809-817 (2019)
  15. Steric Control of the Rate-Limiting Step of UDP-Galactopyranose Mutase. Pierdominici-Sottile G, Cossio-Pérez R, Da Fonseca I, Kizjakina K, Tanner JJ, Sobrado P. Biochemistry 57 3713-3721 (2018)


Quick links