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A universal pocket in Fatty acyl-AMP ligases ensures redirection of fatty acid pool away from Coenzyme A-based activation
eLife ( IF 7.7 ) Pub Date : 2021-09-07 , DOI: 10.7554/elife.70067
Gajanan S Patil 1, 2 , Priyadarshan Kinatukara 1 , Sudipta Mondal 1 , Sakshi Shambhavi 1, 2 , Ketan D Patel 1 , Surabhi Pramanik 1 , Noopur Dubey 1 , Subhash Narasimhan 1 , Murali Krishna Madduri 1 , Biswajit Pal 1 , Rajesh S Gokhale 3 , Rajan Sankaranarayanan 1, 2
Affiliation  

Fatty acyl-AMP ligases (FAALs) channelize fatty acids towards biosynthesis of virulent lipids in mycobacteria and other pharmaceutically or ecologically important polyketides and lipopeptides in other microbes. They do so by bypassing the ubiquitous coenzyme A-dependent activation and rely on the acyl carrier protein-tethered 4'-phosphopantetheine (holo-ACP). The molecular basis of how FAALs strictly reject chemically identical and abundant acceptors like coenzyme A (CoA) and accept holo-ACP unlike other members of the ANL superfamily remains elusive. We show FAALs have plugged the promiscuous canonical CoA-binding pockets and utilize highly selective alternative binding sites. These alternative pockets can distinguish adenosine 3', 5'-bisphosphate-containing CoA from holo-ACP and thus FAALs can distinguish between CoA and holo-ACP. These exclusive features helped identify the omnipresence of FAAL-like proteins and their emergence in plants, fungi, and animals with unconventional domain organisations. The universal distribution of FAALs suggests they are parallelly evolved with FACLs for ensuring a CoA-independent activation and redirection of fatty acids towards lipidic metabolites.

中文翻译:

脂肪酰基-AMP 连接酶中的通用口袋确保将脂肪酸池重定向远离基于辅酶 A 的激活

脂肪酰基-AMP 连接酶 (FAAL) 将脂肪酸引导至分枝杆菌中的毒性脂质和其他微生物中的其他药学或生态学上重要的聚酮化合物和脂肽的生物合成。它们通过绕过无处不在的辅酶 A 依赖性激活并依赖酰基载体蛋白连接的 4'-磷酸泛酰巯基乙胺( holo -ACP) 来实现。FAAL 如何严格拒绝化学相同且丰富的受体,如辅酶 A (CoA) 并与 ANL 超家族的其他成员不同,接受全息-ACP的分子基础仍然难以捉摸。我们展示了 FAAL 已经堵塞了混杂的经典 CoA 结合口袋,并利用了高度选择性的替代结合位点。这些替代口袋可以区分含有腺苷 3'、5'-二磷酸的 CoA 和全息-ACP,因而可以FAALs CoA和区分全息-ACP。这些独特的特征有助于确定 FAAL 样蛋白的普遍存在及其在具有非常规域组织的植物、真菌和动物中的出现。FAAL 的普遍分布表明它们与 FACL 并行进化,以确保不依赖 CoA 的激活和脂肪酸向脂质代谢物的重定向。
更新日期:2021-09-07
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