From lipoic acid to multi‐enzyme complexes

Reed, Lester J.

doi:10.1002/pro.5560070125

Cited by 91 publications

(61 citation statements)

References 14 publications

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“…The 2-oxoacid decarboxylases have been the subject of several excellent reviews (1,2,(14)(15)(16), and thus, only an overview will be given here. These enzyme activities reside in very large, stable protein complexes that catalyze the general reaction depicted in Fig.…”

Section: The Enzymes That Require Attachment Of Lipoic Acidmentioning

confidence: 99%

“…The last name is a relic of the early work in which oxidized and polymerized forms of the molecule were isolated. Lipoic acid acquired its name because it is poorly soluble in water but, like a lipid, is highly soluble in organic solvents (1,2). Indeed, lipoic acid is a derivative of the short-chain fatty acid octanoic acid (Fig.…”

mentioning

confidence: 99%

“…However, acetate-free extracts obtained by acid hydrolysis of liver and yeast also strongly stimulated growth. Extraction into organic solvents concentrated the stimulatory activity, and these preparations were called the acetate replacement factor (1)(2)(3)(4)(5). The most straightforward interpretation was that the factor somehow allowed these bacteria to make their own acetate.…”

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confidence: 99%

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

Cronan

2016

Microbiol Mol Biol Rev

125

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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Section: The Enzymes That Require Attachment Of Lipoic Acidmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Cronan

2016

Microbiol Mol Biol Rev

125

137

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“…Both enzyme complexes participate in glucose oxidation and ATP generation. 3 Studies show that LA administration prevents and attenuates DN in animal models and humans. [4][5][6][7][8][9] However, LA can also act as a pro-oxidant.…”

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confidence: 99%

Reduced Expression of Lipoic Acid Synthase Accelerates Diabetic Nephropathy

Hiller

et al. 2012

Journal of the American Society of Nephrology

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Oxidative stress contributes to the pathogenesis of diabetic nephropathy. In mitochondria, lipoic acid synthase produces a-lipoic acid, an antioxidant and an essential cofactor in a-ketoacid dehydrogenase complexes, which participate in glucose oxidation and ATP generation. Administration of lipoic acid abrogates diabetic nephropathy in animal models, but whether lower production of endogenous lipoic acid promotes diabetic nephropathy is unknown. Here, we crossed mice heterozygous for lipoic acid synthase deficiency (Lias +/2 ) with Ins2 Akita/+ mice, a well characterized model of type 1 diabetes. Double mutant mice had more overt diabetic nephropathy, including microalbuminuria, glomerular basement thickening, mesangial matrix expansion, and hypertension, compared with Lias +/+ Ins2 Akita/+ controls. We also identified proximal tubules as a major site for generation of superoxide anions during diabetic nephropathy. Mitochondria in proximal tubular cells were particularly sensitive to damage in diabetic mice with reduced lipoic acid production. These results suggest that lipoic acid synthase deficiency increases oxidative stress and accelerates the development of diabetic nephropathy.

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“…␣-Lipoic acid functions as a cofactor in multienzyme complexes, including pyruvate dehydrogenase, ␣-ketogutarate dehydrogenase, and branched-chain ␣-ketoacid dehydrogenase (11). ␣-Lipoic acid and its reduced form, dihydrolipoate, are potent antioxidants.…”

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confidence: 99%

α-Lipoic Acid Prevents the Increase in Atherosclerosis Induced by Diabetes in Apolipoprotein E–Deficient Mice Fed High-Fat/Low-Cholesterol Diet

Maeda

2006

Diabetes

105

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Considerable evidence indicates that hyperglycemia increases oxidative stress and contributes to the increased incidence of atherosclerosis and cardiovascular complications in diabetic patients. To examine the effect of ␣-lipoic acid, a potent natural antioxidant, on atherosclerosis in diabetic mice, 3-month-old apolipoprotein (apo) E-deficient (apoE ؊/؊ ) mice were made diabetic by administering streptozotocin (STZ). At 4 weeks after starting the STZ administration, a high-fat diet with or without ␣-lipoic acid (1.65 g/kg) was given to the mice and to nondiabetic apoE ؊/؊ controls. At 20 weeks, markers of oxidative stress were significantly lower in both the diabetic apoE ؊/؊ mice and their nondiabetic apoE ؊/؊ controls with ␣-lipoic acid supplement than in those without it. Remarkably, ␣-lipoic acid completely prevented the increase in plasma total cholesterol, atherosclerotic lesions, and the general deterioration of health caused by diabetes. These protective effects of ␣-lipoic acid were accompanied by a reduction of plasma glucose and an accelerated recovery of insulinproducing cells in the pancreas, suggesting that part of its effects are attributable to protecting pancreatic ␤-cells from damage. Our results suggest that dietary ␣-lipoic acid is a promising protective agent for reducing cardiovascular complications of diabetes. Diabetes

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From lipoic acid to multi‐enzyme complexes

Cited by 91 publications

References 14 publications

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

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

Reduced Expression of Lipoic Acid Synthase Accelerates Diabetic Nephropathy

α-Lipoic Acid Prevents the Increase in Atherosclerosis Induced by Diabetes in Apolipoprotein E–Deficient Mice Fed High-Fat/Low-Cholesterol Diet

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