Structural characterization and comparison of three acyl-carrier-protein synthases from pathogenic bacteria

• Published in: Acta crystallographica. Section D, Biological crystallography. Biological crystallography., 2012-10, Vol.68 (Pt 10)
• Main Authors: Halavaty, Andrei S., Northwestern University, Chicago, IL 60611, Kim, Youngchang, Argonne National Laboratory, Argonne, IL 60439, University of Chicago, Chicago, IL 60637, Minasov, George, Shuvalova, Ludmilla, Dubrovska, Ievgeniia, Winsor, James, Zhou, Min, Onopriyenko, Olena, Skarina, Tatiana, University of Toronto, Toronto, Ontario M5G 1L6, Papazisi, Leka, Kwon, Keehwan, Peterson, Scott N., J. Craig Venter Institute, Rockville, MD 20850, Joachimiak, Andrzej, Savchenko, Alexei, Anderson, Wayne F.
• Format: Article
• Language: English
• Subjects: CARBOXYLIC ACIDS; CARRIERS; CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; CRYSTALS; DELIVERY; DESIGN; INHIBITION; MOLECULES; POTENTIALS; STAPHYLOCOCCUS; SYNTHESIS
• ISSN: 0907-4449; 1399-0047

The structural characterization of acyl-carrier-protein synthase (AcpS) from three different pathogenic microorganisms is reported. One interesting finding of the present work is a crystal artifact related to the activity of the enzyme, which fortuitously represents an opportunity for a strategy to design a potential inhibitor of a pathogenic AcpS. Some bacterial type II fatty-acid synthesis (FAS II) enzymes have been shown to be important candidates for drug discovery. The scientific and medical quest for new FAS II protein targets continues to stimulate research in this field. One of the possible additional candidates is the acyl-carrier-protein synthase (AcpS) enzyme. Its holo form post-translationally modifies the apo form of an acyl carrier protein (ACP), which assures the constant delivery of thioester intermediates to the discrete enzymes of FAS II. At the Center for Structural Genomics of Infectious Diseases (CSGID), AcpSs from Staphylococcus aureus (AcpS{sub SA}), Vibrio cholerae (AcpS{sub VC}) and Bacillus anthracis (AcpS{sub BA}) have been structurally characterized in their apo, holo and product-bound forms, respectively. The structure of AcpS{sub BA} is emphasized because of the two 3′, 5′-adenosine diphosphate (3′, 5′-ADP) product molecules that are found in each of the three coenzyme A (CoA) binding sites of the trimeric protein. One 3′, 5′-ADP is bound as the 3′, 5′-ADP part of CoA in the known structures of the CoA–AcpS and 3′, 5′-ADP–AcpS binary complexes. The position of the second 3′, 5′-ADP has never been described before. It is in close proximity to the first 3′, 5′-ADP and the ACP-binding site. The coordination of two ADPs in AcpS{sub BA} may possibly be exploited for the design of AcpS inhibitors that can block binding of both CoA and ACP.