5frb
Crystal structure of sterol 14-alpha demethylase (CYP51B) from a pathogenic filamentous fungus Aspergillus fumigatus in complex with a tetrazole-based inhibitor VT-1598
Structural highlights
FunctionCP51B_ASPFU Sterol 14alpha-demethylase, encoded by cyp51A and cyp51B, that plays a critical role in the third module of ergosterol biosynthesis pathway, being ergosterol the major sterol component in fungal membranes that participates in a variety of functions (PubMed:18191972, PubMed:26269599, PubMed:26459890, PubMed:29439966, PubMed:9184358). The third module or late pathway involves the ergosterol synthesis itself through consecutive reactions that mainly occur in the endoplasmic reticulum (ER) membrane (By similarity). In filamentous fungi, during the initial step of this module, lanosterol (lanosta-8,24-dien-3beta-ol) can be metabolized to eburicol (PubMed:18191972, PubMed:26459890, PubMed:29439966). Sterol 14alpha-demethylase catalyzes the three-step oxidative removal of the 14alpha-methyl group (C-32) of both these sterols in the form of formate, and converts eburicol and lanosterol to 14-demethyleburicol (4,4,24-trimethylergosta-8,14,24(28)-trienol) and 4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol, respectively, which are further metabolized by other enzymes in the pathway to ergosterol (PubMed:18191972, PubMed:26269599, PubMed:26459890, PubMed:28461309, PubMed:29439966). Can also use substrates not intrinsic to fungi, such as 24,25-dihydrolanosterol (DHL), producing 4,4'-dimethyl-8,14-cholestadien-3-beta-ol, but at lower rates than the endogenous substrates (By similarity).[UniProtKB:P10614][1] [2] [3] [4] [5] [6] As a target of azole drugs, plays a crucial role in azole susceptibility.[7] [8] [9] [10] Publication Abstract from PubMedWithin the past decades, the incidence and complexity of human fungal infections have increased, and therefore the need for safer and more efficient, broad-spectrum antifungal agents is high. Herein, we characterize the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14alpha-demethylase (CYP51B) from the filamentous fungi Aspergillus fumigatus VT-1598 displayed a high binding affinity to the enzyme in solution (with the Kd of 13+/-1 nM) and in the reconstituted enzymatic reaction revealed the inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatus CYP51 complex has been determined depicting the distinctive binding mode of the inhibitor in the enzyme active site and suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His-374, the CYP51 residue that is highly conserved across fungal pathogens and fungi-specific. Comparative structural analysis of A. fumigatus CYP51/voriconazole and C. albicans CYP51/VT-1161 complexes supports the role of H-bonding in fungal CYP51-inhibitor complexes, and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using two A. fumigatus strains (32820 and 1022) displayed direct correlation between the effects of the drugs on the CYP51B activity and fungal growth inhibition, indicating the noteworthy anti-A. fumigatus potency of VT-1598 and confirming its promise as a broad-spectrum antifungal agent. Crystal structure of the new investigational drug candidate VT-1598 in complex with Aspergillus fumigatus sterol 14alpha-demethylase provides insights into its broad-spectrum antifungal activity.,Hargrove TY, Garvey EP, Hoekstra WJ, Yates CM, Wawrzak Z, Rachakonda G, Villalta F, Lepesheva GI Antimicrob Agents Chemother. 2017 May 1. pii: AAC.00570-17. doi:, 10.1128/AAC.00570-17. PMID:28461309[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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