Crystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis Journal Article

  

Authors:	Rajashankar, K. R.; Bryk, R.; Kniewel, R.; Buglino, J. A.; Nathan, C. F.; Lima, C. D.
Article Title:	Crystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis
Abstract:	We report the 2.4 Å crystal structure for lipoamide dehydrogenase encoded by lpdC from Mycobacterium tuberculosis. Based on the Lpd structure and sequence alignment between bacterial and eukaryotic Lpd sequences, we generated single point mutations in Lpd and assayed the resulting proteins for their ability to catalyze lipoamide reduction/oxidation alone and in complex with other proteins that participate in pyruvate dehydrogenase and peroxidase activities. The results suggest that amino acid residues conserved in mycobacterial species but not conserved in eukaryotic Lpd family members modulate either or both activities and include Arg-93, His-98, Lys-103, and His-386. In addition, Arg-93 and His-386 are involved in forming both "open" and "closed" active site conformations, suggesting that these residues play a role in dynamically regulating Lpd function. Taken together, these data suggest protein surfaces that should be considered while developing strategies for inhibiting this enzyme. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.
Keywords:	nonhuman; protein conformation; peroxidase; gene; enzyme inhibition; structure activity relation; structure-activity relationship; bacteria (microorganisms); mycobacterium tuberculosis; amino acid sequence; molecular sequence data; sequence alignment; eukaryota; nucleotide sequence; crystal structure; amino acids; enzyme kinetics; sequence homology; point mutation; enzyme structure; mutagenesis; dna, bacterial; oxidation reduction reaction; lysine; arginine; histidine; sequence analysis, dna; conformations; pyruvate dehydrogenase; lipoamide dehydrogenase; dihydrolipoamide dehydrogenase; bacteria; surface property; functional analysis; amino acid derivative; encoding (symbols); eukaryotic sequences; myobacterial species; lpdc gene
Journal Title:	Journal of Biological Chemistry
Volume:	280
Issue:	40
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Date Published:	2005-10-07
Start Page:	33977
End Page:	33983
Language:	English
DOI:	10.1074/jbc.M507466200
PUBMED:	16093239
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-26644432063&partnerID=40&md5=9014fa6cfcf5ade4710172bc240b84b1
Notes:	--- - "Cited By (since 1996): 15" - "Export Date: 24 October 2012" - "CODEN: JBCHA" - "Molecular Sequence Numbers: GENBANK: O08749, O53747, P09622, P09623, P49819, Q50068;" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/35719