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Invariance and variability in bacterial PanK: a study based on the crystal structure of Mycobacterium tuberculosis PanK.

Das S, Kumar P, Bhor V, Surolia A, Vijayan M
Acta Crystallogr D Biol Crystallogr 62 628-38 (2006)
Related entries: 2get, 2geu, 2gev

Cited: 19 times
EuropePMC logo PMID: 16699190

Abstract

Pantothenate kinase (PanK) is a ubiquitous and essential enzyme that catalyzes the first step of the universal coenzyme A biosynthetic pathway. In this step, pantothenate (vitamin B(5)) is converted to 4'-phosphopantothenate, which subsequently forms coenzyme A in four enzymatic steps. The complex of this enzyme from Mycobacterium tuberculosis (MtPanK) with a derivative of the feedback inhibitor coenzyme A has been crystallized in two forms and its structure solved. The structure was refined in both forms using room-temperature and low-temperature X-ray data. In both forms, the MtPanK subunit has a mononucleotide-binding fold with a seven-stranded central beta-sheet and helices on either side. However, there is a small though significant difference in subunit association between the two forms. The structure is also grossly similar to the enzyme from Escherichia coli. The active-site pocket and the dimeric interface are on two opposite sides of the PanK subunit. The enzymes from M. tuberculosis and E. coli exhibit several differences, particularly at the dimeric interface. On the other hand, the coenzyme A-binding region is almost entirely conserved. A delineation of the invariant and variable features of the PanK structure further indicates that the dimeric interface is very variable, while the coenzyme A-binding site is substantially invariant. A sequence alignment involving various bacterial PanKs is in agreement with this conclusion. The strong correlation between structural plasticity, evolutionary conservation and variability and function exhibited by the molecule could be important in the design of species-specific inhibitors of the enzyme.

Articles - 2ges mentioned but not cited (2)

  1. Structural and biochemical characterization of compounds inhibiting Mycobacterium tuberculosis pantothenate kinase. Björkelid C, Bergfors T, Raichurkar AK, Mukherjee K, Malolanarasimhan K, Bandodkar B, Jones TA. J Biol Chem 288 18260-18270 (2013)
  2. Assessment of Mycobacterium tuberculosis pantothenate kinase vulnerability through target knockdown and mechanistically diverse inhibitors. Reddy BK, Landge S, Ravishankar S, Patil V, Shinde V, Tantry S, Kale M, Raichurkar A, Menasinakai S, Mudugal NV, Ambady A, Ghosh A, Tunduguru R, Kaur P, Singh R, Kumar N, Bharath S, Sundaram A, Bhat J, Sambandamurthy VK, Björkelid C, Jones TA, Das K, Bandodkar B, Malolanarasimhan K, Mukherjee K, Ramachandran V. Antimicrob Agents Chemother 58 3312-3326 (2014)


Reviews citing this publication (4)

  1. Coenzyme A biosynthesis: an antimicrobial drug target. Spry C, Kirk K, Saliba KJ. FEMS Microbiol Rev 32 56-106 (2008)
  2. The application of tetracyclineregulated gene expression systems in the validation of novel drug targets in Mycobacterium tuberculosis. Evans JC, Mizrahi V. Front Microbiol 6 812 (2015)
  3. Recent advances in targeting coenzyme A biosynthesis and utilization for antimicrobial drug development. Moolman WJ, de Villiers M, Strauss E. Biochem Soc Trans 42 1080-1086 (2014)
  4. Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents. Butman HS, Kotzé TJ, Dowd CS, Strauss E. Front Cell Infect Microbiol 10 605662 (2020)

Articles citing this publication (13)

  1. targetTB: a target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis. Raman K, Yeturu K, Chandra N. BMC Syst Biol 2 109 (2008)
  2. Structural plasticity and enzyme action: crystal structures of mycobacterium tuberculosis peptidyl-tRNA hydrolase. Selvaraj M, Roy S, Singh NS, Singh NS, Sangeetha R, Varshney U, Vijayan M. J Mol Biol 372 186-193 (2007)
  3. A multitarget approach to drug discovery inhibiting Mycobacterium tuberculosis PyrG and PanK. Chiarelli LR, Mori G, Orena BS, Esposito M, Lane T, de Jesus Lopes Ribeiro AL, Degiacomi G, Zemanová J, Szádocka S, Huszár S, Palčeková Z, Manfredi M, Gosetti F, Lelièvre J, Ballell L, Kazakova E, Makarov V, Marengo E, Mikusova K, Cole ST, Riccardi G, Ekins S, Pasca MR. Sci Rep 8 3187 (2018)
  4. Essentiality and functional analysis of type I and type III pantothenate kinases of Mycobacterium tuberculosis. Awasthy D, Ambady A, Bhat J, Sheikh G, Ravishankar S, Subbulakshmi V, Mukherjee K, Sambandamurthy V, Sharma U. Microbiology (Reading) 156 2691-2701 (2010)
  5. Screening, identification, and characterization of mechanistically diverse inhibitors of the Mycobacterium tuberculosis enzyme, pantothenate kinase (CoaA). Venkatraman J, Bhat J, Solapure SM, Sandesh J, Sarkar D, Aishwarya S, Mukherjee K, Datta S, Malolanarasimhan K, Bandodkar B, Das KS. J Biomol Screen 17 293-302 (2012)
  6. The role of UPF0157 in the folding of M. tuberculosis dephosphocoenzyme A kinase and the regulation of the latter by CTP. Walia G, Kumar P, Surolia A. PLoS One 4 e7645 (2009)
  7. Molecular Docking Suggests the Targets of Anti-Mycobacterial Natural Products. Baptista R, Bhowmick S, Shen J, Mur LAJ. Molecules 26 475 (2021)
  8. Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase. Awuah E, Ma E, Hoegl A, Vong K, Habib E, Auclair K. Bioorg Med Chem 22 3083-3090 (2014)
  9. A novel heteromeric pantothenate kinase complex in apicomplexan parasites. Tjhin ET, Howieson VM, Spry C, van Dooren GG, Saliba KJ. PLoS Pathog 17 e1009797 (2021)
  10. Location and conformation of pantothenate and its derivatives in Mycobacterium tuberculosis pantothenate kinase: insights into enzyme action. Chetnani B, Kumar P, Abhinav KV, Chhibber M, Surolia A, Vijayan M. Acta Crystallogr D Biol Crystallogr 67 774-783 (2011)
  11. Development of new antituberculous agents based on new drug targets and structure-activity relationship. Tomioka H. Expert Opin Drug Discov 3 21-49 (2008)
  12. An Indian effort towards affordable drugs: "generic to designer drugs". Taneja B, Yadav J, Chakraborty TK, Brahmachari SK. Biotechnol J 4 348-360 (2009)
  13. Structural studies on M. tuberculosis argininosuccinate lyase and its liganded complex: Insights into catalytic mechanism. Paul A, Mishra A, Surolia A, Vijayan M. IUBMB Life 71 643-652 (2019)


Related citations provided by authors (1)

  1. Expression, purification, crystallization and preliminary X-ray crystallographic analysis of pantothenate kinase from Mycobacterium tuberculosis.. Das S, Kumar P, Bhor V, Surolia A, Vijayan M Acta Crystallogr Sect F Struct Biol Cryst Commun 61 65-7 (2005)

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