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Development and Retention of a Primordial Moonlighting Pathway of Protein Modification in the Absence of Selection Presents a Pu

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Development and Retention of a Primordial Moonlighting Pathway of Protein Modification in the Absence of Selection Presents a Pu Development and retention of a primordial INAUGURAL ARTICLE moonlighting pathway of protein modification in the absence of selection presents a puzzle Xinyun Caoa,1, Yaoqin Hongb,1, Lei Zhub,2, Yuanyuan Hua, and John E. Cronana,b,3 aDepartment of Biochemistry, University of Illinois at Urbana–Champagne, Urbana, IL 61801; and bDepartment of Microbiology, University of Illinois at Urbana–Champagne, Urbana, IL 61801 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2017. Contributed by John E. Cronan, December 7, 2017 (sent for review October 25, 2017; reviewed by Sean T. Prigge and Eric Smith) Lipoic acid is synthesized by a remarkably atypical pathway in which sulfur protein, LipA. LipA donates two sulfur atoms to carbons 6 and the cofactor is assembled on its cognate proteins. An octanoyl 8 of octanoate to give a dihydrolipoyl moiety which becomes oxidized moiety diverted from fatty acid synthesis is covalently attached to to lipoyl-LD (Fig. 1A). Hence, lipoic acid is an atypical enzyme co- the acceptor protein, and sulfur insertion at carbons 6 and 8 of the factor in that it is assembled on its cognate proteins rather than being octanoyl moiety form the lipoyl cofactor. Covalent attachment of this wholly assembled before its covalent attachment, as is the case with cofactor is required for function of several central metabolism biotin, another covalently attached coenzyme (5). enzymes, including the glycine cleavage H protein (GcvH). In Bacillus The straightforward two-enzyme, LipB plus LipA, E. coli lip- subtilis, GcvH is the sole substrate for lipoate assembly. Hence lipoic oate synthesis pathway is found in many, but not all, bacterial acid-requiring 2-oxoacid dehydrogenase (OADH) proteins acquire the species. A more complex pathway is found in Bacillus subtilis (6– cofactor only by transfer from lipoylated GcvH. Lipoyl transfer has been 9). The impetus to study this bacterium was the lack of a gene Escher- argued to be the primordial pathway of OADH lipoylation. The encoding a LipB homolog (6), although a validated LipA homolog ichia coli pathway where lipoate is directly assembled on both its GcvH was present (9). Moreover, the B. subtilis genome encoded what BIOCHEMISTRY and OADH proteins, is proposed to have arisen later. Because roughly appeared to be three lipoate ligase homologs, the paradigm of 3 billion years separate the divergence of these bacteria, it is surprising which, E. coli LplA, scavenges lipoate from the environment (8). that E. coli GcvH functionally substitutes for the B. subtilis protein in Screening of a plasmid library of B. subtilis genome fragments for lipoyl transfer. Known and putative GcvHs from other bacteria and eukaryotes also substitute for B. subtilis GcvH in OADH modification. complementation of an E. coli strain lacking LipB gave one of the Because glycine cleavage is the primary GcvH role in ancestral bacteria putative lipoate ligase genes. However, the gene encoded an that lack OADH enzymes, lipoyl transfer is a “moonlighting” function: octanoyl transferase called LipM that had no ligase activity and that is, development of a new function while retaining the original virtually no sequence resemblance to E. coli LipB (6). Another function. This moonlighting has been conserved in the absence of putative lipoate ligase gene (LplJ) encoded a true lipoate ligase, selection by some, but not all, GcvH proteins. Moreover, Aquifex aeo- licus encodes five putative GcvHs, two of which have the moonlighting Significance function, whereas others function only in glycine cleavage. The LipB–LipA and lipoyl-relay pathways seem restricted to lipoic acid | glycine cleavage | enzyme moonlighting | aerobic gram-negative and gram-positive bacteria, respectively. metabolism | C1 metabolism Braakman and Smith have persuasively argued that the lipoyl- relay pathway involving transfer of lipoic acid from lipoylated ipoic acid is an essential sulfur-containing coenzyme required GcvH is the primordial pathway and that the LipB–LipA path- Lby key enzymes of central metabolism in all three domains of way arose later. The chemically challenging nature of lipoyl life (1, 2). Unlike most coenzymes, lipoic acid functions only after transfer strengthens this argument. Given the roughly 3 billion covalent attachment to its cognate enzyme proteins. These are the years since the two groups of bacteria diverged, it is un- E2 subunits of the 2-oxoacid dehydrogenase (OADH) complexes expected and puzzling that the lipoyl transfer properties of and the H proteins (called GcvH or GcsH, depending on the or- many GcvHs—those from eukaryotes and bacteria, including ganism) of the glycine cleavage system (glycine decarboxylase in Escherichia coli, and the deep-branching hyperthermophilic Aquifex aeolicus— plants), all of which have been well studied (1). Although the OADH chemoautotrophic bacterium, have lipoyl- Bacillus subtilis lipoyl domains (LDs) and the GcvH proteins both contain a strictly relay activity in . This provides a remarkable “ ” conserved lysine residue to which lipoic acid is attached and have case in which a protein moonlighting function is found remarkably similar structures, the proteins have only low sequence throughout evolution without selection for the function. identities (1, 3). Lipoic acid attachment to these proteins is via an Author contributions: X.C., Y. Hong, and J.E.C. designed research; X.C., Y. Hong, L.Z., and amide linkage formed between the lipoic acid carboxyl group and Y. Hu performed research; L.Z. and Y. Hu contributed new reagents/analytic tools; Y. Hong the conserved lysine e-amino group (1, 3). Once attached, the lipoyl and J.E.C. analyzed data; and X.C. and J.E.C. wrote the paper. moiety becomes competent for enzyme catalysis. The terminal Reviewers: S.T.P., The Johns Hopkins Bloomberg School of Public Health; and E.S., Santa dithiolane ring becomes reduced and acylated with a reaction in- Fe Institute. termediate and the lipoyl-lysine arm serves to shuttle reaction inter- The authors declare no conflict of interest. mediates between the active sites of the multienzyme complexes (3). Published under the PNAS license. Lipoic acid assembly is best understood in Escherichia coli,where 1X.C. and Y. Hong contributed equally to this work. only two enzymes are required. LipB, an octanoyl transferase trans- 2Present address: College of Life Sciences, Shandong Agricultural University, Taian, fers the octanoyl moiety from fatty acid biosynthetic intermediate 271018 Shandong, China. octanoyl-acyl carrier protein (ACP), to the specific lysine side chain of 3To whom correspondence should be addressed. Email: [email protected]. GcvH or an OADH LD (1, 4). The resulting octanoyl-protein is a This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. substrate for the sulfur insertion step catalyzed by the radical iron- 1073/pnas.1718653115/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1718653115 PNAS Early Edition | 1of9 Downloaded by guest on September 30, 2021 Fig. 1. Lipoic acid synthesis and scavenging in E. coli and B. subtilis.(A) The E. coli lipoic acid synthetic pathway requires only two proteins, LipB and LipA. The LipB octanoyl-ACP transferase transfers the octanoyl moiety from the fatty acid biosynthetic intermediate, octanoyl-ACP, to both OADH LDs and GcvH, where LipA-catalyzed sulfur insertion converts the octanoyl moiety to lipoate. (B) The B. subtilis lipoic acid synthetic pathway requires four proteins (three enzymes plus the GcvH protein, on which lipoate is assembled and donated to the OADH proteins) rather than the two enzymes of the simpler E. coli pathway (A). Like E. coli, B. subtilis has the LipA sulfur insertion enzyme and an octanoyl transferase, LipM, although LipM is an isozyme rather than a homolog of the E. coli LipB octanoyl transferase. The octanoylated GcvH then becomes a substrate for LipA-catalyzed sulfur insertion at carbons 6 and 8, as in A. The lipoyl moiety is then relayed from GcvH to the OADH subunits by an amidotransferase called LipL. (C) Both bacteria scavenge lipoate from the medium by use of the reaction shown for the E. coli lipoate ligase, LplA. The B. subtilis ligase is LplJ (8). The ligases (which are 33% identical) are required for lipoate supplementation of strains blocked in lipoic acid synthesis. E. coli LplA efficiently lipoylates both its cognate GcvH and the OADH domains (43), whereas in B. subtilis GcvH is a much better substrate for LplJ than are the OADH proteins (8). whereas the third putative lipoate ligase gene (lipL) remained an LDs. Indeed when LipL, the third putative B. subtilis lipoate li- enigma, although it was essential for lipoate synthesis (8). The gase, was purified, the protein lacked ligase activity but was found enzymological characterization of LipM presented a quandary in to transfer an octanoyl moiety from its amide linkage on GcvH to that the purified enzyme was unable to transfer octanoate from the PDH LD using an acyl-enzyme (acyl-cysteine) intermediate octanoyl-ACP to its cognate pyruvate dehydrogenase (PDH) LDs, (7). These biochemical experiments argued that GcvH was an although the proteins were good substrates for the E. coli LipB obligate intermediate in lipoylation of the B. subtilis OADH octanoyl transferase (7). A concern was the possibility that LipM proteins, and therefore B. subtilis ΔgcvH strains should be unable recognition of the B. subtilis PDH domains required assembly of to make lipoate and be auxotrophic for lipoate. This was the case: the E2 subunit into the very large PDH complexes that contain the small GcvH protein is required for both lipoylation of the many copies of E2, plus the E1 and E3 subunits. To avoid the B. subtilis subunits (PDH for aerobic metabolism and the branched- possibility of a complex being the substrate, GcvH, a protein of chain OADH for fatty acid synthesis) and for glycine cleavage (7).
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