Biosynthesis of lipoic acid. 2. Stereochemistry of sulfur introduction at C-6 of octanoic acid

Parry, Ronald J.; Trainor, Diane A.

doi:10.1021/ja00484a073

Cited by 57 publications

(33 citation statements)

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“…In the second step of LA biosynthesis two sulfur atoms are inserted at the C6 and C8 positions by an iron-sulfur lipoic acid synthase enzyme, LipA ( Figure 1A -reaction B2) (15)(16)(17). This step is similar to biotin synthesis in that the reaction mechanism requires sulfur donation from an [4Fe-4S] cluster within the enzyme and reductive cleavage of s-adenosylmethionine (SAM) to generate 5'deoxyadenosyl 5'-radicals (5'-dA • ) that remove a hydrogen atom from C6 and C8 and facilitate insertion of the sulfur atoms (5,18,19).…”

Section: Lipoic Acid Synthesismentioning

confidence: 99%

Lipoic acid metabolism and mitochondrial redox regulation

Solmonson

DeBerardinis

2018

Journal of Biological Chemistry

334

255

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Lipoic acid is an essential cofactor for mitochondrial metabolism and is synthesized de novo using intermediates from mitochondrial fatty acid synthesis type II, S-adenosylmethionine and iron-sulfur clusters. This cofactor is required for catalysis by multiple mitochondrial 2-ketoacid dehydrogenase complexes, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain ketoacid dehydrogenase. Lipoic acid also plays a critical role in stabilizing and regulating these multienzyme complexes. Many of these dehydrogenases are regulated by reactive oxygen species, mediated through the disulfide bond of the prosthetic lipoyl moiety.Collectively, its functions explain why lipoic acid is required for cell growth, mitochondrial activity and coordination of fuel metabolism.

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Section: Lipoic Acid Synthesismentioning

confidence: 99%

Lipoic acid metabolism and mitochondrial redox regulation

Solmonson

DeBerardinis

2018

Journal of Biological Chemistry

334

255

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“…Early studies established that octanoic acid (Fig. 1) is the precursor of the lipoic acid carbon chain (92,93). Analysis of the conversion of specifically labeled forms of octanoic acid to lipoic acid by E. coli cultures showed that the two sulfur atoms are introduced with the loss of only two hydrogen atoms from the chain, one from C-6 and the other from C-8 (92).…”

Section: Biosynthesis Of Lipoic Acidmentioning

confidence: 99%

Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway

Cronan

2016

Microbiol Mol Biol Rev

128

137

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SUMMARYAlthough the structure of lipoic acid and its role in bacterial metabolism were clear over 50 years ago, it is only in the past decade that the pathways of biosynthesis of this universally conserved cofactor have become understood. Unlike most cofactors, lipoic acid must be covalently bound to its cognate enzyme proteins (the 2-oxoacid dehydrogenases and the glycine cleavage system) in order to function in central metabolism. Indeed, the cofactor is assembled on its cognate proteins rather than being assembled and subsequently attached as in the typical pathway, like that of biotin attachment. The first lipoate biosynthetic pathway determined was that ofEscherichia coli, which utilizes two enzymes to form the active lipoylated protein from a fatty acid biosynthetic intermediate. Recently, a more complex pathway requiring four proteins was discovered inBacillus subtilis, which is probably an evolutionary relic. This pathway requires the H protein of the glycine cleavage system of single-carbon metabolism to form active (lipoyl) 2-oxoacid dehydrogenases. The bacterial pathways inform the lipoate pathways of eukaryotic organisms. Plants use theE. colipathway, whereas mammals and fungi probably use theB. subtilispathway. The lipoate metabolism enzymes (except those of sulfur insertion) are members of PFAM family PF03099 (the cofactor transferase family). Although these enzymes share some sequence similarity, they catalyze three markedly distinct enzyme reactions, making the usual assignment of function based on alignments prone to frequent mistaken annotations. This state of affairs has possibly clouded the interpretation of one of the disorders of human lipoate metabolism.

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“…Furthermore, there is increasing evidence that mammals can synthesize lipoate (258). In organisms that generate lipoate endogenously, the cofactor is synthesized from an octanoic acid precursor (168), with stereospecific insertion of the sulfur atom at carbon six to yield the R enantiomer, which is the biologically active form (169).…”

Section: Historical Overview Of Lipoic Acid Discoverymentioning

confidence: 99%

Lipoic Acid Metabolism in Microbial Pathogens

Spalding

Prigge

2010

Microbiol Mol Biol Rev

167

204

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SUMMARY Lipoic acid [(R)-5-(1,2-dithiolan-3-yl)pentanoic acid] is an enzyme cofactor required for intermediate metabolism in free-living cells. Lipoic acid was discovered nearly 60 years ago and was shown to be covalently attached to proteins in several multicomponent dehydrogenases. Cells can acquire lipoate (the deprotonated charge form of lipoic acid that dominates at physiological pH) through either scavenging or de novo synthesis. Microbial pathogens implement these basic lipoylation strategies with a surprising variety of adaptations which can affect pathogenesis and virulence. Similarly, lipoylated proteins are responsible for effects beyond their classical roles in catalysis. These include roles in oxidative defense, bacterial sporulation, and gene expression. This review surveys the role of lipoate metabolism in bacterial, fungal, and protozoan pathogens and how these organisms have employed this metabolism to adapt to niche environments.

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Biosynthesis of lipoic acid. 2. Stereochemistry of sulfur introduction at C-6 of octanoic acid

Cited by 57 publications

References 1 publication

Lipoic acid metabolism and mitochondrial redox regulation

Lipoic acid metabolism and mitochondrial redox regulation

Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway

Lipoic Acid Metabolism in Microbial Pathogens

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