Active site structure and substrate specificity of cytochrome P450 4A1: steric control of ligand approach perpendicular to heme plane

Biochemical and Biophysical Research Communications
R B Bambal, R P Hanzlik

Abstract

The active site of an engineered, expressed fusion protein containing the sequences of cytochrome P450 4A1 (lauric acid omega-hydroxylase) and NADPH-cytochrome P450 reductase, has been probed with olefinic, acetylenic, aromatic, and other analogs of its normal substrate. The fusion protein omega-hydroxylates lauric acid, epoxidizes 11-dodocenoic acid, oxidizes 11-dodecynoic acid to 1,12-dodecandioic acid, but does not oxidize 9-phenylnonanoic acid. Nevertheless, the latter is a tight-binding Type I ligand (Ks = 0.77 microM) and a potent inhibitor of lauric acid hydroxylation. These and other observations are used to construct an active site model that accounts for its remarkable substrate and inhibitor specificity.

Citations

Nov 26, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jonathan B JohnstonPaul R Ortiz de Montellano
Mar 23, 2011·Drug Metabolism and Pharmacokinetics·Yoshiyuki YamauraYasushi Yamazoe
Feb 20, 2002·FEBS Letters·Michail A Alterman, Robert P Hanzlik
Jul 24, 2020·PloS One·Torsten DiesingerThomas Haehner
Oct 12, 2017·Frontiers in Pharmacology·Tsveta StoyanovaStanislav Yanev
Jun 11, 1999·The American Journal of Physiology·X NguyenM L Schwartzman
Aug 24, 2010·Archives of Biochemistry and Biophysics·Jonathan B JohnstonPaul R Ortiz de Montellano

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.