| Structural highlights
Function
[CBR1_HUMAN] NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol. Can convert prostaglandin E2 to prostaglandin F2-alpha. Can bind glutathione, which explains its higher affinity for glutathione-conjugated substrates. Catalyzes the reduction of S-nitrosoglutathione.[1] [2] [3] [4]
Publication Abstract from PubMed
The NADPH-dependent human carbonyl reductase 1 (hCBR1), a member of the short-chain dehydrogenase/reductase protein family, plays an important role in the ubiquitous metabolism of endogenous and xenobiotic carbonyl containing compounds. Glutathione (GSH) is also a cofactor of hCBR1, however, its role in the carbonyl reductase function of the enzyme is still unclear. In this study, we presented the crystal structure of hCBR1 in complex with GSH, in the absence of its substrates or inhibitors. Interestingly, we found that the GSH molecule presents in a configuration quite different from that was previously reported when substrate is binding to hCBR1. Our structure indicates that GSH contributes to the substrate selectivity of hCBR1 and protects the catalytic center of hCBR1 through a switch-like mechanism. The isothermal titration calorimetry and enzymology data shows that GSH directly binding with hCBR1 when there's no substrate exist. The enzymology data also shows GSH protects NADPH being attacked by oxidative small molecules. This is the first time that GSH is found to demonstrate such functions as a co-enzyme. Our crystal structure succeeds in providing critical insights into the substrate selectivity of hCBR1 and the interaction between hCBR1 and GSH.
Structural insights on the catalytic site protection of human carbonyl reductase 1 by glutathione.,Liang Q, Liu R, Du S, Ding Y J Struct Biol. 2015 Oct;192(1):138-44. doi: 10.1016/j.jsb.2015.09.005. Epub 2015 , Sep 14. PMID:26381805[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gonzalez-Covarrubias V, Kalabus JL, Blanco JG. Inhibition of polymorphic human carbonyl reductase 1 (CBR1) by the cardioprotectant flavonoid 7-monohydroxyethyl rutoside (monoHER). Pharm Res. 2008 Jul;25(7):1730-4. doi: 10.1007/s11095-008-9592-5. Epub 2008 May, 1. PMID:18449627 doi:http://dx.doi.org/10.1007/s11095-008-9592-5
- ↑ Tanaka M, Bateman R, Rauh D, Vaisberg E, Ramachandani S, Zhang C, Hansen KC, Burlingame AL, Trautman JK, Shokat KM, Adams CL. An unbiased cell morphology-based screen for new, biologically active small molecules. PLoS Biol. 2005 May;3(5):e128. Epub 2005 Apr 5. PMID:15799708 doi:10.1371/journal.pbio.0030128
- ↑ Bateman R, Rauh D, Shokat KM. Glutathione traps formaldehyde by formation of a bicyclo[4.4.1]undecane adduct. Org Biomol Chem. 2007 Oct 21;5(20):3363-7. Epub 2007 Aug 29. PMID:17912391 doi:10.1039/b707602a
- ↑ Bateman RL, Rauh D, Tavshanjian B, Shokat KM. Human carbonyl reductase 1 is an S-nitrosoglutathione reductase. J Biol Chem. 2008 Dec 19;283(51):35756-62. Epub 2008 Sep 29. PMID:18826943 doi:10.1074/jbc.M807125200
- ↑ Liang Q, Liu R, Du S, Ding Y. Structural insights on the catalytic site protection of human carbonyl reductase 1 by glutathione. J Struct Biol. 2015 Oct;192(1):138-44. doi: 10.1016/j.jsb.2015.09.005. Epub 2015 , Sep 14. PMID:26381805 doi:http://dx.doi.org/10.1016/j.jsb.2015.09.005
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