9ZW6

Structure of the HMG-CoA reductase from Borrelia burgdorferi bound to HMG-CoA

Summary for 9ZW6

• Entry DOI: 10.2210/pdb9zw6/pdb
• Descriptor: Probable 3-hydroxy-3-methylglutaryl-coenzyme A reductase, 3-HYDROXY-3-METHYLGLUTARYL-COENZYME A (3 entities in total)
• Functional Keywords: class ii hmgr, bacterial, isoprenoid biosynthesis, oxidoreductase
• Biological source: Borreliella burgdorferi B31
• Total number of polymer chains: 2
• Total formula weight: 101438.13

Authors

Paddy, I.,Dassma, L.M.K. (deposition date: 2026-01-01, release date: 2026-09-02)

Primary citation

Paddy, I.A.,McCausland, J.,Frazier, M.,Chatterjee, P.,Setegne, M.,Eidam, O.,Jacobs-Wagner, C.,Dassama, L.M.K.
A cofactor-promiscuous HMGR from the Lyme disease pathogen illuminates diversity in bacterial isoprenoid biosynthesis.
Protein Sci., 35:e70766-e70766, 2026

PubMed Abstract: The Lyme disease pathogen Borrelia burgdorferi contains a highly reduced genome lacking many primary metabolic pathways. However, B. burgdorferi retains the mevalonate pathway that synthesizes isopentenyl pyrophosphate (IPP), the precursor to the peptidoglycan carrier lipid. While the mevalonate pathway and the enzyme that catalyzes its rate-limiting step (3-hydroxy-3-methyl glutaryl coenzyme A reductase, HMGR) are well studied in vertebrates, little is known about the pathway in B. burgdorferi and many pathogenic bacteria. In this work, we reveal that HMGR is a critical metabolic enzyme in B. burgdorferi. We demonstrate that loss of HMGR causes morphological defects and muted de novo synthesis of peptidoglycan; these defects are ameliorated by exogenous mevalonate and IPP. Biochemical characterization unveiled HMGR as a highly unusual cofactor-promiscuous oxidoreductase that functions with both nicotinamide cofactors. Bioinformatics and biochemical characterization uncovered examples of similarly promiscuous HMGRs and revealed a previously unrecognized evolutionary link to cofactor choice. Moreover, structures of the enzyme reveal a highly divergent active site architecture. Together, these findings firmly establish HMGR as an opportunity target for the development of antibacterials for a diderm pathogen while highlighting cofactor promiscuity as an evolutionary acquired feature in HMGRs.

PubMed: 42615804
DOI: 10.1002/pro.70766

Experimental method

X-RAY DIFFRACTION (2.55 Å)