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Title: Cytochrome P450BM-3 reduces aldehydes to alcohols through a direct hydride transfer

Abstract

Highlights: Black-Right-Pointing-Pointer Cytochrome P450BM-3 reduced aldehydes to alcohols efficiently (k{sub cat} {approx} 25 min{sup -1}). Black-Right-Pointing-Pointer Reduction is a direct hydride transfer from R-NADP{sup 2}H to the carbonyl moiety. Black-Right-Pointing-Pointer P450 domain variants enhance reduction through potential allosteric/redox interactions. Black-Right-Pointing-Pointer Novel reaction will have implications for metabolism of xenobiotics. -- Abstract: Cytochrome P450BM-3 catalyzed the reduction of lipophilic aldehydes to alcohols efficiently. A k{sub cat} of {approx}25 min{sup -1} was obtained for the reduction of methoxy benzaldehyde with wild type P450BM-3 protein which was higher than in the isolated reductase domain (BMR) alone and increased in specific P450-domain variants. The reduction was caused by a direct hydride transfer from preferentially R-NADP{sup 2}H to the carbonyl moiety of the substrate. Weak substrate-P450-binding of the aldehyde, turnover with the reductase domain alone, a deuterium incorporation in the product from NADP{sup 2}H but not D{sub 2}O, and no inhibition by imidazole suggests the reductase domain of P450BM-3 as the potential catalytic site. However, increased aldehyde reduction by P450 domain variants (P450BM-3 F87A T268A) may involve allosteric or redox mechanistic interactions between heme and reductase domains. This is a novel reduction of aldehydes by P450BM-3 involving a direct hydride transfer and could have implicationsmore » for the metabolism of endogenous substrates or xenobiotics.« less

Authors:
; ;  [1]
  1. Department of Medicinal Chemistry, University of Washington, Box 357610, Seattle, WA 98195-7610 (United States)
Publication Date:
OSTI Identifier:
22207706
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 418; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALCOHOLS; BACILLUS MEGATERIUM; BENZALDEHYDE; CARBONYLS; DEUTERIUM; ENZYMES; HEAVY WATER; HEME; HYDRIDES; INHIBITION; METABOLISM; NADP; XENOBIOTICS

Citation Formats

Kaspera, Ruediger, Sahele, Tariku, Lakatos, Kyle, and Totah, Rheem A., E-mail: rtotah@u.washington.edu. Cytochrome P450BM-3 reduces aldehydes to alcohols through a direct hydride transfer. United States: N. p., 2012. Web. doi:10.1016/J.BBRC.2012.01.040.
Kaspera, Ruediger, Sahele, Tariku, Lakatos, Kyle, & Totah, Rheem A., E-mail: rtotah@u.washington.edu. Cytochrome P450BM-3 reduces aldehydes to alcohols through a direct hydride transfer. United States. https://doi.org/10.1016/J.BBRC.2012.01.040
Kaspera, Ruediger, Sahele, Tariku, Lakatos, Kyle, and Totah, Rheem A., E-mail: rtotah@u.washington.edu. 2012. "Cytochrome P450BM-3 reduces aldehydes to alcohols through a direct hydride transfer". United States. https://doi.org/10.1016/J.BBRC.2012.01.040.
@article{osti_22207706,
title = {Cytochrome P450BM-3 reduces aldehydes to alcohols through a direct hydride transfer},
author = {Kaspera, Ruediger and Sahele, Tariku and Lakatos, Kyle and Totah, Rheem A., E-mail: rtotah@u.washington.edu},
abstractNote = {Highlights: Black-Right-Pointing-Pointer Cytochrome P450BM-3 reduced aldehydes to alcohols efficiently (k{sub cat} {approx} 25 min{sup -1}). Black-Right-Pointing-Pointer Reduction is a direct hydride transfer from R-NADP{sup 2}H to the carbonyl moiety. Black-Right-Pointing-Pointer P450 domain variants enhance reduction through potential allosteric/redox interactions. Black-Right-Pointing-Pointer Novel reaction will have implications for metabolism of xenobiotics. -- Abstract: Cytochrome P450BM-3 catalyzed the reduction of lipophilic aldehydes to alcohols efficiently. A k{sub cat} of {approx}25 min{sup -1} was obtained for the reduction of methoxy benzaldehyde with wild type P450BM-3 protein which was higher than in the isolated reductase domain (BMR) alone and increased in specific P450-domain variants. The reduction was caused by a direct hydride transfer from preferentially R-NADP{sup 2}H to the carbonyl moiety of the substrate. Weak substrate-P450-binding of the aldehyde, turnover with the reductase domain alone, a deuterium incorporation in the product from NADP{sup 2}H but not D{sub 2}O, and no inhibition by imidazole suggests the reductase domain of P450BM-3 as the potential catalytic site. However, increased aldehyde reduction by P450 domain variants (P450BM-3 F87A T268A) may involve allosteric or redox mechanistic interactions between heme and reductase domains. This is a novel reduction of aldehydes by P450BM-3 involving a direct hydride transfer and could have implications for the metabolism of endogenous substrates or xenobiotics.},
doi = {10.1016/J.BBRC.2012.01.040},
url = {https://www.osti.gov/biblio/22207706}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 418,
place = {United States},
year = {Fri Feb 17 00:00:00 EST 2012},
month = {Fri Feb 17 00:00:00 EST 2012}
}