 | Acta Crystallographica Section F Acta Crystallographica Section F STRUCTURAL BIOLOGY COMMUNICATIONS |
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Figure 1
Overview of microbial de novo fatty-acid synthesis. (a) Synthetic machineries for fatty-acid production in bacteria and fungi. The grey background highlights the compartmentalized synthesis of acyl-CoA by the multifunctional FAS I systems. Key steps in the catalytic cycle of FAS I-mediated synthesis are as follows. The central ketoacyl synthase (KS) domain condenses ac(et)yl with malonyl to form β-ketobutyryl. Further, the compound is reduced by a ketoacyl reductase (KR) to β-hydroxyacyl, dehydrated by a dehydratase (DH) to produce enoyl, and again reduced by an enoyl reductase (ER). Substrate CoA esters are turned into ACP esters by transferases. ACPs (boxes in magenta) then shuttle substrates and intermediates to the active sites of the catalytic domains. Note that in FAS I, ACPs are part of the multienzyme. Also note that MPT (malonyl palmitoyl transferase) in fungal FAS I loads malonyl and unloads palmitoyl, and MAT (malonyl acyl transferase) in bacteria loads malonyl and unloads acyl chains of various chain lengths. The terminal thiol group of ACP is indicated to highlight that substrates and intermediates are provided as thioesters. Product specificities for corynebacterial, mycobacterial and fungal FAS I systems are given as reported in this study (C. efficiens FAS I) and previously: C. ammoniagenes FAS I (Stuible et al., 1997  ), M. tuberculosis and M. smegmatis FAS I (Kikuchi et al., 1992; Zimhony et al., 2004; Peterson & Bloch, 1977) and Saccharomyces cerevisiae FAS I (Sumper et al., 1969; Kresze et al., 1977). Separate proteins of the FAS II are labelled as occurring in M. tuberculosis fatty-acid synthesis (Gago et al., 2011; Bhatt et al., 2007; Sacco et al., 2007). Pharmaceutically relevant inhibitors of M. tuberculosis fatty-acid synthesis are included in the scheme: pyrazinamide (PZA; Sayahi et al., 2011), isoxyl (ISO; Gannoun-Zaki et al., 2013), thiolactomycin (TLM; Kremer et al., 2000), isoniazid (INH), ethionamide (ETH) and triclosan (TRC) (Sullivan et al., 2006; Banerjee et al., 1994). (b) Phylogenetic analysis of selected bacterial and fungal FAS I. For the calculation of the phylogenetic tree, dual-chain fungal FAS I were submitted as β/α-fused pseudo-single chains. For the analysis, FAS I with the following GenBank accession Nos. were used: Candida albicans (X74952.1, L29063.1), Saccharomyces cerevisiae (CAA82025.1, CAA97948.1), Cryptococcus neoformans (AAW43793.1, AAW43793.1), Ustilago maydis (XP_759118.1), Corynebacterium glutamicum (YP_225128), C. efficiens (NP_739002.1), C. ammoniagenes (CAA46024.1), Gordonia terrae (WP_004019558.1), G. amicalis (WP_024498183.1), Mycobacterium smegmatis (AAO43178.1), M. tuberculosis (NP_217040), M. bovis (NP_856198.1), Nocardia asteroides (WP_019045581.1), N. brasiliensis (GAJ86521.1), Rhodococcus wratislaviensis (GAF47416.1) and R. rhodochrous (ETT26757.1). Analysis was performed using the neighbour-joining algorithm with the Jones–Taylor–Thornton substitution model using the Ugene software package (Okonechnikov et al., 2012). |
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| STRUCTURAL BIOLOGY COMMUNICATIONS |
ISSN: 2053-230X
