Light‐Wavelength‐Based Quantitative Control of Dihydrofolate Reductase Activity by Using a Photochromic Isostere of an Inhibitor. (3rd April 2019)

• Record Type: Journal Article
• Authors: Mashita, Takato; Kowada, Toshiyuki; Takahashi, Hiroto; Matsui, Toshitaka; Mizukami, Shin
• Is Part Of: Chembiochem. Volume 20:Number 11(2019)
• Page Start: 1382
• Page End: 1386
• Publication Date: 2019-04-03
• Subjects: azobenzenes -- enzyme catalysis -- inhibitors -- methotrexate -- photochromism -- photopharmacology; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201800816
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Photopharmacology has attracted research attention as a new tool for achieving optical control of biomolecules, following the methods of caged compounds and optogenetics. We have developed an efficient photopharmacological inhibitor—azoMTX—for Escherichia coli dihydrofolate reductase (eDHFR) by replacing some atoms of the original ligand, methotrexate, to achieve photoisomerization properties. This fine molecular design enabled quick structural conversion between the active "bent" Z isomer of azoMTX and the inactive "extended" E isomer, and this property afforded quantitative control over the enzyme activity, depending on the wavelength of irradiating light applied. Real‐time photoreversible control over enzyme activity was also achieved. Abstract : Optical tuning of dihydrofolate reductase activity : AzoMTX is an azo isostere of methotrexate (MTX), an inhibitor of E . coli dihydrofolate reductase (eDHFR). ( E )‐AzoMTX inhibits the enzyme catalysis slightly, whereas ( Z )‐azoMTX inhibits it strongly. The inhibition efficiency was controlled in a manner dependent on the light wavelength, with real‐time reversible control of eDHFR activity also being achieved.