Functional characterization of the first lipoyl-relay pathway from a parasitic protozoan.

Publisher: Blackwell Scientific Publications Country of Publication: England NLM ID: 8712028 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2958 (Electronic) Linking ISSN: 0950382X NLM ISO Abbreviation: Mol Microbiol Subsets: MEDLINE

Original Publication: Oxford, OX ; Boston, MA : Blackwell Scientific Publications, c1987-

Metabolic Networks and Pathways*/genetics ; Thioctic Acid*/metabolism ; Trypanosoma brucei brucei*/genetics ; Trypanosoma brucei brucei*/metabolism; Bacillus subtilis/metabolism ; Ligases/metabolism ; Saccharomyces cerevisiae/metabolism

Lipoic acid (LA) is a sulfur-containing cofactor covalently attached to key enzymes of central metabolism in prokaryotes and eukaryotes. LA can be acquired by scavenging, mediated by a lipoate ligase, or de novo synthesized by a pathway requiring an octanoyltransferase and a lipoate synthase. A more complex pathway, referred to as "lipoyl-relay", requires two additional proteins, GcvH, the glycine cleavage system H subunit, and an amidotransferase. This route was described so far in Bacillus subtilis and related Gram-positive bacteria, Saccharomyces cerevisiae, Homo sapiens, and Caenorhabditis elegans. Using collections of S. cerevisiae and B. subtilis mutants, defective in LA metabolism, we gathered evidence that allows us to propose for the first time that lipoyl-relay pathways are also present in parasitic protozoa. By a reverse genetic approach, we assigned octanoyltransferase and amidotransferase activity to the products of Tb927.11.9390 (TblipT) and Tb927.8.630 (TblipL) genes of Trypanosoma brucei, respectively. The B. subtilis model allowed us to identify the parasite amidotransferase as the target of lipoate analogs like 8-bromo-octanoic acid, explaining the complete loss of protein lipoylation and growth impairment caused by this compound in T. cruzi. This model could be instrumental for the screening of selective and more efficient chemotherapies against trypanosomiases.
(© 2022 John Wiley & Sons Ltd.)

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Keywords: amidotransferase; chemotherapy; lipoic acid; trypanosomatids

73Y7P0K73Y (Thioctic Acid)
EC 6.- (Ligases)

Date Created: 20220429 Date Completed: 20220628 Latest Revision: 20220719

20240829

10.1111/mmi.14913

35484915