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Structure-Function Analysis of the Acyl Carrier Protein Synthase (AcpS) from Mycobacterium tuberculosis |
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| Authors: | Orly Dym Shira Albeck Yoav Peleg Alon Schwarz Yigal Burstein |
| Affiliation: | 1 Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel 2 Israel Structural Proteomics Center, Weizmann Institute of Science, Rehovot 76100, Israel 3 Department of Organic Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel 4 Kaplan Medical Center, affiliated to the Hebrew University, Rehovot 76100, Israel |
| Abstract: | We have solved the crystal structure of the acyl carrier protein synthase (AcpS) from Mycobacterium tuberculosis (Mtb) at 1.95 Å resolution. AcpS, a 4-phosphopantetheinyl transferase, activates two distinct acyl carrier proteins (ACPs) that are present in fatty acid synthase (FAS) systems FAS-I and FAS-II, the ACP-I domain and the mycobacterial ACP-II protein (ACPM), respectively. Mtb, the causal agent of tuberculosis (TB), and all other members of the Corynebacterineae family are unique in possessing both FAS systems to produce and to elongate fatty acids to mycolic acids, the hallmark of mycobacterial cell wall. Various steps in this process are prime targets for first-line anti-TB agents. A comparison of the Mtb AcpS structure determined here with those of other AcpS proteins revealed unique structural features in Mtb AcpS, namely, the presence of an elongated helix followed by a flexible loop and a moderately electronegative surface unlike the positive surface common to other AcpSs. A structure-based sequence comparison between AcpS and its ACP substrates from various species demonstrated that the proteins of the Corynebacterineae family display high sequence conservation, forming a segregated subgroup of AcpS and ACPs. Analysis of the putative interactions between AcpS and ACPM from Mtb, based on a comparison with the complex structure from Bacillus subtilis, showed that the Mtb AcpS and ACPM lack the electrostatic complementarity observed in B. subtilis. Taken together, the common characteristic of the Corynebacterineae family is likely reflected in the participation of different residues and interactions used for binding the Mtb AcpS to ACP-I and ACPM. The distinct features and essentiality of AcpS, as well as the mode of interaction with ACPM and ACP-I in Mtb, could be exploited for the design of AcpS inhibitors, which, similarly to other inhibitors of fatty acid synthesis, are expected to be effective anti-TB-specific drugs. |
| Keywords: | AcpS, acyl carrier protein synthase Mtb, Mycobacterium tuberculosis ACP, acyl carrier protein FAS, fatty acid synthase ACPM, mycobacterial ACP-II protein TB, tuberculosis CoA, coenzyme A P-pant, 4&prime -phosphatepantetheinyl PPT, phosphopantetheine transferase PDB, Protein Data Bank SeMet, selenomethionine MAD, multiple anomalous dispersion |
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