Biotin and Lipoic Acid: Synthesis, Attachment, and Regulation

Abstract

SummaryTwo vitamins, biotin and lipoic acid, are essential in all three domains of life. Both coenzymes function only when covalently attached to key metabolic enzymes. There they act as "swinging arms" that shuttle intermediates between two active sites (= covalent substrate channeling) of key metabolic enzymes. Although biotin was discovered over 100 years ago and lipoic acid 60 years ago, it was not known how either coenzyme is made until recently. In Escherichia coli the synthetic pathways for both coenzymes have now been worked out for the first time.The late steps of biotin synthesis, those involved in assembling the fused rings, were welldescribed biochemically years ago, although recent progress has been made on the BioB reaction, the last step of the pathway in which the biotin sulfur moiety is inserted. In contrast, the early steps of biotin synthesis, assembly of the fatty acid-like "arm" of biotin were unknown. It has now been demonstrated that the arm is made by using disguised substrates to gain entry into the fatty acid synthesis pathway followed by removal of the disguise when the proper chain length is attained. The BioC methyltransferase is responsible for introducing the disguise and the BioH esterase for its removal.In contrast to biotin, which is attached to its cognate proteins as a finished molecule, lipoic acid is assembled on its cognate proteins. An octanoyl moiety is transferred from the octanoyl-ACP of fatty acid synthesis to a specific lysine residue of a cognate protein by the LipB octanoyl transferase followed by sulfur insertion at carbons C6 and C8 by the LipA lipoyl synthetase. Assembly on the cognate proteins regulates the amount of lipoic acid synthesized and thus there is no transcriptional control of the synthetic genes. In contrast transcriptional control of the biotin synthetic genes is wielded by a remarkably sophisticated, yet simple, system, exerted through BirA a dual function protein that both represses biotin operon transcription and ligates biotin to its cognate protein.

Enterococcus faecalis Encodes an Atypical Auxiliary Acyl Carrier Protein Required for Efficient Regulation of Fatty Acid Synthesis by Exogenous Fatty Acids

“…Fatty acid synthesis (FAS) is a key metabolic pathway that provides precursors for the formation of cellular membranes in mammals, plants, fungi, and bacteria (1). Moreover, the fatty acid synthesis pathway allows diversion of intermediates to other functional molecules such as the vitamins biotin and lipoic acid (2) plus various bacterial signaling molecules (3). Fatty acid synthesis in bacteria, mitochondria, and plant plastids is catalyzed by a set of discrete enzymes that are collectively known as the type II (FAS II) system (1).…”

Activity Mapping the Acyl Carrier Protein: Elongating Ketosynthase Interaction in Fatty Acid Biosynthesis

“…-INTRODUCTION-Fatty acid biosynthesis (FAB) is a primary metabolic pathway in prokaryotes and eukaryotes, serving as a central biosynthetic hub for precursors utilized in membrane development and homeostasis, energy storage, cofactor biosynthesis, and signaling. [1][2][3][4][5][6][7][8] FAB involves the iterative condensation and reduction of two carbon acetyl-CoA derived units, with each round of chain elongation requiring four separate chemical reactions. (Figure 1a).…”

“…Fatty acid biosynthesis (FAB) is a primary metabolic pathway in prokaryotes and eukaryotes, serving as a central biosynthetic hub for precursors utilized in membrane development and homeostasis, energy storage, cofactor biosynthesis, and signaling. − FAB involves the iterative condensation and reduction of two carbon acetyl-CoA-derived units, with each round of chain elongation requiring four separate chemical reactions (Figure a). , The first step of each cycle is carbon–carbon bond formation via a KS-mediated Claisen-like condensation reaction between two ketide units to produce a β-keto intermediate. Subsequent reactions by the ketoreductase (KR), dehydratase (DH), and enoylreductase (ER) catalyze overall reduction of the β-position before another round of chain extension occurs.…”

A Novel Gene Contributing to the Initiation of Fatty Acid Biosynthesis in Escherichia coli

“…Our data are consistent with the idea that the initiation of fatty acid biosynthesis in the absence of FabH activity was fabY mediated and that the growth defects of the ΔfabH ⌬fabY, ppGpp 0 ΔfabH, and ΔdksA ⌬fabH strains arise from the abrogation of the initiation of fatty acid biosynthesis, specifically the loss of acetoacetyl-ACP synthesis. In addition to phospholipids, acetoacetyl-ACP is required for the synthesis of essential molecules such as lipid A and coenzyme lipoic acid (1,52). Therefore, if the synthesis of acetoacetyl-ACP was blocked in the ΔfabH ⌬fabY, ppGpp 0 ΔfabH, or ΔdksA ⌬fabH mutant, we expected that the growth defect of these strains could not be rescued by palmitate and oleate.…”