Structure-Function Analysis of the Essential Mycobacterium tuberculosis P450 Drug Target, CYP121A1.

Abstract

Cytochrome P450 CYP121A1 is a well-known drug target against Mycobacterium tuberculosis, the human pathogen that causes the deadly disease tuberculosis (TB). CYP121A1 is a unique P450 enzyme because it uses classical and non-classical P450 catalytic processes and has distinct structural features among P450s. However, a detailed investigation of CYP121A1 protein structures in terms of active site cavity dynamics and key amino acids interacting with bound ligands has yet to be undertaken. To address this research knowledge gap, 53 CYP121A1 crystal structures were investigated in this study. Critical amino acids required for CYP121A1's overall activity were identified and highlighted this enzyme's rigid architecture and substrate selectivity. The CYP121A1-fluconazole crystal structure revealed a novel azole drug-P450 binding mode in which azole heme coordination was facilitated by a water molecule. Fragment-based inhibitor approaches revealed that CYP121A1 can be inhibited by molecules that block the substrate channel or by directly interacting with the P450 heme. This study serves as a reference for the precise understanding of CYP121A1 interactions with different ligands and the structure-function analysis of P450 enzymes in general. Our findings provide critical information for the synthesis of more specific CYP121A1 inhibitors and their development as novel anti-TB drugs.

• Authors: Tiara Padayachee, David C Lamb, David R Nelson, Khajamohiddin Syed
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 25 Issue 9 (Apr 30 2024) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 38732102 (Publication Type: Journal Article)

Chemical References

• Cytochrome P-450 Enzyme System
• cytochrome P-450 CYP121
• Antitubercular Agents
• Bacterial Proteins
• Cytochrome P-450 Enzyme Inhibitors
• Ligands

Topics

• Mycobacterium tuberculosis (enzymology, drug effects)
• Cytochrome P-450 Enzyme System (metabolism, chemistry)
• Structure-Activity Relationship
• Catalytic Domain
• Antitubercular Agents (pharmacology, chemistry)
• Bacterial Proteins (metabolism, chemistry, antagonists & inhibitors)
• Crystallography, X-Ray
• Cytochrome P-450 Enzyme Inhibitors (pharmacology, chemistry)
• Models, Molecular
• Humans
• Protein Binding
• Substrate Specificity
• Ligands
• Protein Conformation