2022 journal article

Self-sacrificial tyrosine cleavage by an Fe:Mn oxygenase for the biosynthesis of para-aminobenzoate in Chlamydia trachomatis

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 119(39).

By: O. Manley n, H. Phan n, A. Stewart n, D. Mosley n, S. Xue*, L. Cha n, H. Bai n, V. Lightfoot* ...

co-author countries: United States of America 🇺🇸
author keywords: folate biosynthesis; radical transfer; spectroscopy; heterobinuclear cluster
MeSH headings : Bacterial Proteins / metabolism; Chlamydia trachomatis / enzymology; Folic Acid; Iron / metabolism; Manganese / metabolism; Oxygen / metabolism; Oxygenases / metabolism; Tyrosine / metabolism; para-Aminobenzoates / metabolism
Source: Web Of Science
Added: May 30, 2023

Chlamydia protein associating with death domains (CADD) is involved in the biosynthesis of para -aminobenzoate (pABA), an essential component of the folate cofactor that is required for the survival and proliferation of the human pathogen Chlamydia trachomatis . The pathway used by Chlamydiae for pABA synthesis differs from the canonical multi-enzyme pathway used by most bacteria that relies on chorismate as a metabolic precursor. Rather, recent work showed pABA formation by CADD derives from l -tyrosine. As a member of the emerging superfamily of heme oxygenase–like diiron oxidases (HDOs), CADD was proposed to use a diiron cofactor for catalysis. However, we report maximal pABA formation by CADD occurs upon the addition of both iron and manganese, which implicates a heterobimetallic Fe:Mn cluster is the catalytically active form. Isotopic labeling experiments and proteomics studies show that CADD generates pABA from a protein-derived tyrosine (Tyr27), a residue that is ∼14 Å from the dimetal site. We propose that this self-sacrificial reaction occurs through O 2 activation by a probable Fe:Mn cluster through a radical relay mechanism that connects to the “substrate” Tyr, followed by amination and direct oxygen insertion. These results provide the molecular basis for pABA formation in C. trachomatis , which will inform the design of novel therapeutics.