| Structural highlights
Function
DLDH_MYCTU Lipoamide dehydrogenase is an essential component of the alpha-ketoacid dehydrogenase complexes, namely the pyruvate dehydrogenase (PDH) complex, the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, and likely also the 2-oxoglutarate dehydrogenase (ODH) complex. Catalyzes the reoxidation of dihydrolipoyl groups which are covalently attached to the lipoate acyltransferase components (E2) of the complexes. Is also able to catalyze the transhydrogenation of NADH and thio-NAD(+) in the absence of D,L-lipoamide, and the NADH-dependent reduction of quinones in vitro.[1] [2] [3] [4] [5] Together with AhpC, AhpD and DlaT, Lpd constitutes an NADH-dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system.[6] [7] [8] [9] [10] Appears to be essential for Mtb pathogenesis.[11] [12] [13] [14] [15]
Publication Abstract from PubMed
Lpd (lipoamide dehydrogenase) in Mycobacterium tuberculosis (Mtb) is required for virulence and is a genetically validated tuberculosis (TB) target. Numerous screens have been performed over the last decade, yet only two inhibitor series have been identified. Recent advances in large-scale virtual screening methods combined with make-on-demand compound libraries have shown the potential for finding novel hits. In this study, the Enamine REAL library consisting of approximately 1.12 billion compounds was efficiently screened using the GPU Shape screen method against Mtb Lpd to find additional chemical matter that would expand on the known sulfonamide inhibitor series. We identified six new inhibitors with IC(50) in the range of 5-100 muM. While these compounds remained chemically close to the already known sulfonamide series inhibitors, some diversity was found in the cores of the hits. The two most potent hits were further validated by one-step potency optimization to submicromolar levels. The co-crystal structure of optimized analogue TDI-13537 provided new insights into the potency determinants of the series.
Shape-Based Virtual Screening of a Billion-Compound Library Identifies Mycobacterial Lipoamide Dehydrogenase Inhibitors.,Michino M, Beautrait A, Boyles NA, Nadupalli A, Dementiev A, Sun S, Ginn J, Baxt L, Suto R, Bryk R, Jerome SV, Huggins DJ, Vendome J ACS Bio Med Chem Au. 2023 Sep 8;3(6):507-515. doi: , 10.1021/acsbiomedchemau.3c00046. eCollection 2023 Dec 20. PMID:38144256[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Argyrou A, Blanchard JS. Mycobacterium tuberculosis lipoamide dehydrogenase is encoded by Rv0462 and not by the lpdA or lpdB genes. Biochemistry. 2001 Sep 25;40(38):11353-63. PMID:11560483
- ↑ Bryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C. Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science. 2002 Feb 8;295(5557):1073-7. Epub 2002 Jan 17. PMID:11799204 doi:10.1126/science.1067798
- ↑ Tian J, Bryk R, Shi S, Erdjument-Bromage H, Tempst P, Nathan C. Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. Mol Microbiol. 2005 Aug;57(3):859-68. PMID:16045627 doi:http://dx.doi.org/MMI4741
- ↑ Venugopal A, Bryk R, Shi S, Rhee K, Rath P, Schnappinger D, Ehrt S, Nathan C. Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe. 2011 Jan 20;9(1):21-31. doi: 10.1016/j.chom.2010.12.004. PMID:21238944 doi:http://dx.doi.org/10.1016/j.chom.2010.12.004
- ↑ Rajashankar KR, Bryk R, Kniewel R, Buglino JA, Nathan CF, Lima CD. Crystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis. J Biol Chem. 2005 Oct 7;280(40):33977-83. Epub 2005 Aug 10. PMID:16093239 doi:10.1074/jbc.M507466200
- ↑ Argyrou A, Blanchard JS. Mycobacterium tuberculosis lipoamide dehydrogenase is encoded by Rv0462 and not by the lpdA or lpdB genes. Biochemistry. 2001 Sep 25;40(38):11353-63. PMID:11560483
- ↑ Bryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C. Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science. 2002 Feb 8;295(5557):1073-7. Epub 2002 Jan 17. PMID:11799204 doi:10.1126/science.1067798
- ↑ Tian J, Bryk R, Shi S, Erdjument-Bromage H, Tempst P, Nathan C. Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. Mol Microbiol. 2005 Aug;57(3):859-68. PMID:16045627 doi:http://dx.doi.org/MMI4741
- ↑ Venugopal A, Bryk R, Shi S, Rhee K, Rath P, Schnappinger D, Ehrt S, Nathan C. Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe. 2011 Jan 20;9(1):21-31. doi: 10.1016/j.chom.2010.12.004. PMID:21238944 doi:http://dx.doi.org/10.1016/j.chom.2010.12.004
- ↑ Rajashankar KR, Bryk R, Kniewel R, Buglino JA, Nathan CF, Lima CD. Crystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis. J Biol Chem. 2005 Oct 7;280(40):33977-83. Epub 2005 Aug 10. PMID:16093239 doi:10.1074/jbc.M507466200
- ↑ Argyrou A, Blanchard JS. Mycobacterium tuberculosis lipoamide dehydrogenase is encoded by Rv0462 and not by the lpdA or lpdB genes. Biochemistry. 2001 Sep 25;40(38):11353-63. PMID:11560483
- ↑ Bryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C. Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science. 2002 Feb 8;295(5557):1073-7. Epub 2002 Jan 17. PMID:11799204 doi:10.1126/science.1067798
- ↑ Tian J, Bryk R, Shi S, Erdjument-Bromage H, Tempst P, Nathan C. Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. Mol Microbiol. 2005 Aug;57(3):859-68. PMID:16045627 doi:http://dx.doi.org/MMI4741
- ↑ Venugopal A, Bryk R, Shi S, Rhee K, Rath P, Schnappinger D, Ehrt S, Nathan C. Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe. 2011 Jan 20;9(1):21-31. doi: 10.1016/j.chom.2010.12.004. PMID:21238944 doi:http://dx.doi.org/10.1016/j.chom.2010.12.004
- ↑ Rajashankar KR, Bryk R, Kniewel R, Buglino JA, Nathan CF, Lima CD. Crystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis. J Biol Chem. 2005 Oct 7;280(40):33977-83. Epub 2005 Aug 10. PMID:16093239 doi:10.1074/jbc.M507466200
- ↑ Michino M, Beautrait A, Boyles NA, Nadupalli A, Dementiev A, Sun S, Ginn J, Baxt L, Suto R, Bryk R, Jerome SV, Huggins DJ, Vendome J. Shape-Based Virtual Screening of a Billion-Compound Library Identifies Mycobacterial Lipoamide Dehydrogenase Inhibitors. ACS Bio Med Chem Au. 2023 Sep 8;3(6):507-515. PMID:38144256 doi:10.1021/acsbiomedchemau.3c00046
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