Work

Structures of Mycobacterium tuberculosis FadD10 Protein Reveal a New Type of Adenylate-forming Enzyme

Year: 2013

Type: article

Abstract: Mycobacterium tuberculosis has a group of 34 FadD proteins that belong to the adenylate-forming superfamily. They are classified as either fatty acyl-AMP ligases (FAALs) or fatty acyl-CoA ligases based on sequence analysis. FadD10, involved in the synthesis of a virulence-related lipopeptide, was mis-annotated as a fatty acyl-CoA ligase; however, it is in fact a FAAL that transfers fatty acids to an acyl carrier protein (Rv0100). In this study, we have determined the structures of FadD10 in both the apo-form and the complexed form with dodecanoyl-AMP, where we see for the first time an adenylate-forming enzyme that does not adopt a closed conformation for catalysis. Indeed, this novel conformation of FadD10, facilitated by its unique inter-domain and intermolecular interactions, is critical for the enzyme to carry out the acyl transfer onto Rv0100 rather than coenzyme A. This contradicts the existing model of FAALs that rely on an insertion motif for the acyltransferase specificity and thus makes FadD10 a new type of FAAL. We have also characterized the fatty acid preference of FadD10 through biological and structural analyses, and the data indicate long chain saturated fatty acids as the biological substrates of the enzyme. Background: Mycobacterium tuberculosis FadD10 transfers fatty acyl chains onto an acyl carrier protein via adenylated intermediates. Results: The structures of M. tuberculosis FadD10 reveal a ligand-bound conformation previously unseen in the adenylate-forming superfamily. Conclusion: The structures of M. tuberculosis FadD10 provide a novel structural basis for the enzyme's function compared with the homologues. Significance: Fatty acyl transfer is an important biological process involved in the synthesis of bioactive lipopeptides.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m113.466912

Authors: Zhen Liu, Thomas R. Ioerger, Feng Wang, James C. Sacchettini

Institutions: Texas A&M University, California Institute for Biomedical Research

Language: English

Topic: Enzyme Structure and Function

Subfield: Materials Chemistry

Field: Materials Science

Domain: Physical Sciences

Open Access status: hybrid

Estimated APC paid: $3,430

Funders: U.S. Public Health Service, National Institute of Allergy and Infectious Diseases