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The crystal structure of Mycobacterium tuberculosis alkylhydroperoxidase AhpD, a potential target for antitubercular drug design.

Nunn CM, Djordjevic S, Hillas PJ, Nishida CR, Ortiz de Montellano PR
J Biol Chem 277 20033-40 (2002)
Cited: 26 times
EuropePMC logo PMID: 11914371

Abstract

The resistance of Mycobacterium tuberculosis to isoniazid is commonly linked to inactivation of a catalase-peroxidase, KatG, that converts isoniazid to its biologically active form. Loss of KatG is associated with elevated expression of the alkylhydroperoxidases AhpC and AhpD. AhpD has no sequence identity with AhpC or other proteins but has alkylhydroperoxidase activity and possibly additional physiological activities. The alkylhydroperoxidase activity, in the absence of KatG, provides an important antioxidant defense. We have determined the M. tuberculosis AhpD structure to a resolution of 1.9 A. The protein is a trimer in a symmetrical cloverleaf arrangement. Each subunit exhibits a new all-helical protein fold in which the two catalytic sulfhydryl groups, Cys-130 and Cys-133, are located near a central cavity in the trimer. The structure supports a mechanism for the alkylhydroperoxidase activity in which Cys-133 is deprotonated by a distant glutamic acid via the relay action of His-137 and a water molecule. The cysteine then reacts with the peroxide to give a sulfenic acid that subsequently forms a disulfide bond with Cys-130. The crystal structure of AhpD identifies a new protein fold relevant to members of this protein family in other organisms. The structural details constitute a potential platform for the design of inhibitors of potential utility as antitubercular agents and suggest that AhpD may have disulfide exchange properties of importance in other areas of M. tuberculosis biology.

Articles - 1gu9 mentioned but not cited (5)

  1. Crystal structure of alkyl hydroperoxidase D like protein PA0269 from Pseudomonas aeruginosa: homology of the AhpD-like structural family. Clarke TE, Romanov V, Chirgadze YN, Klomsiri C, Kisselman G, Wu-Brown J, Poole LB, Pai EF, Chirgadze NY. BMC Struct. Biol. 11 27 (2011)
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  3. Roles of RcsA, an AhpD Family Protein, in Reactive Chlorine Stress Resistance and Virulence in Pseudomonas aeruginosa. Nontaleerak B, Duang-Nkern J, Wongsaroj L, Trinachartvanit W, Romsang A, Mongkolsuk S. Appl Environ Microbiol 86 e01480-20 (2020)
  4. Structure of lpg0406, a carboxymuconolactone decarboxylase family protein possibly involved in antioxidative response from Legionella pneumophila. Chen X, Hu Y, Yang B, Gong X, Zhang N, Niu L, Wu Y, Ge H. Protein Sci. 24 2070-2075 (2015)
  5. Structure-function analyses of alkylhydroperoxidase D from Streptococcus pneumoniae reveal an unusual three-cysteine active site architecture. Meng Y, Sheen CR, Magon NJ, Hampton MB, Dobson RCJ. J Biol Chem 295 2984-2999 (2020)


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  1. Evolution of protein fold in the presence of functional constraints. Andreeva A, Murzin AG. Curr. Opin. Struct. Biol. 16 399-408 (2006)
  2. Mycothiol-dependent proteins in actinomycetes. Rawat M, Av-Gay Y. FEMS Microbiol. Rev. 31 278-292 (2007)
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  4. Techniques and applications: The heterologous expression of Mycobacterium tuberculosis genes is an uphill road. Bellinzoni M, Riccardi G. Trends Microbiol. 11 351-358 (2003)
  5. The pathogenic mechanism of Mycobacterium tuberculosis: implication for new drug development. Yan W, Zheng Y, Dou C, Zhang G, Arnaout T, Cheng W. Mol Biomed 3 48 (2022)

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  3. Crystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis. Rajashankar KR, Bryk R, Kniewel R, Buglino JA, Nathan CF, Lima CD. J Biol Chem 280 33977-33983 (2005)
  4. Text mining improves prediction of protein functional sites. Verspoor KM, Cohn JD, Ravikumar KE, Wall ME. PLoS ONE 7 e32171 (2012)
  5. An operon in Streptococcus pneumoniae containing a putative alkylhydroperoxidase D homologue contributes to virulence and the response to oxidative stress. Paterson GK, Blue CE, Mitchell TJ. Microb. Pathog. 40 152-160 (2006)
  6. Intermolecular interactions in the AhpC/AhpD antioxidant defense system of Mycobacterium tuberculosis. Koshkin A, Knudsen GM, Ortiz De Montellano PR. Arch. Biochem. Biophys. 427 41-47 (2004)
  7. Enzymatic Reductive Dehalogenation Controls the Biosynthesis of Marine Bacterial Pyrroles. El Gamal A, Agarwal V, Rahman I, Moore BS. J. Am. Chem. Soc. 138 13167-13170 (2016)
  8. NikD, an unusual amino acid oxidase essential for nikkomycin biosynthesis: structures of closed and open forms at 1.15 and 1.90 A resolution. Carrell CJ, Bruckner RC, Venci D, Zhao G, Jorns MS, Mathews FS. Structure 15 928-941 (2007)
  9. Crystal structure of the conserved protein TTHA0727 from Thermus thermophilus HB8 at 1.9 A resolution: A CMD family member distinct from carboxymuconolactone decarboxylase (CMD) and AhpD. Ito K, Arai R, Fusatomi E, Kamo-Uchikubo T, Kawaguchi S, Akasaka R, Terada T, Kuramitsu S, Shirouzu M, Yokoyama S. Protein Sci. 15 1187-1192 (2006)
  10. Inhibition of Mycobacterium tuberculosis AhpD, an element of the peroxiredoxin defense against oxidative stress. Koshkin A, Zhou XT, Kraus CN, Brenner JM, Bandyopadhyay P, Kuntz ID, Barry CE, Ortiz de Montellano PR. Antimicrob. Agents Chemother. 48 2424-2430 (2004)
  11. Dihydrophenylalanine: a prephenate-derived Photorhabdus luminescens antibiotic and intermediate in dihydrostilbene biosynthesis. Crawford JM, Mahlstedt SA, Malcolmson SJ, Clardy J, Walsh CT. Chem. Biol. 18 1102-1112 (2011)
  12. A novel alkyl hydroperoxidase (AhpD) of Anabaena PCC7120 confers abiotic stress tolerance in Escherichia coli. Shrivastava AK, Singh S, Singh PK, Pandey S, Rai LC. Funct. Integr. Genomics 15 77-92 (2015)
  13. Response of Pseudomonas aeruginosa to the Innate Immune System-Derived Oxidants Hypochlorous Acid and Hypothiocyanous Acid. Farrant KV, Spiga L, Davies JC, Williams HD. J Bacteriol 203 e00300-20 (2020)
  14. Bacterial Tetrabromopyrrole Debrominase Shares a Reductive Dehalogenation Strategy with Human Thyroid Deiodinase. Chekan JR, Lee GY, El Gamal A, Purdy TN, Houk KN, Moore BS. Biochemistry 58 5329-5338 (2019)
  15. Preparation and Characterization of Tetrabromopyrrole Debrominase From Marine Proteobacteria. Chekan JR, Moore BS. Meth. Enzymol. 605 253-265 (2018)
  16. The ahpD gene of Corynebacterium glutamicum plays an important role in hydrogen peroxide-induced oxidative stress response. Hong EJ, Jeong H, Lee DS, Kim Y, Lee HS. J. Biochem. 165 197-204 (2019)


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