The Formation of CoA from Pantothenic Acid

CoA functions as the carrier of fatty acids, as thioesters, in mitochondrial p-oxidation. The resultant two-carbon fragments, as acetyl CoA, then undergo oxidation in the citric acid cycle. CoA also functions as a carrier in the transfer of fatty acyl groups in a variety of biosynthetic and catabolic reactions, including steroidogenesis; long-chain fatty acid synthesis from palmitate in mitochondria and endoplasmic reticulum; monounsaturation of palmitoyl CoA to palmitoleyl CoA (C16:1 «9) and stearyl CoA to oleyl CoA (C18:1 «9); elongation of polyunsaturated fatty acids; acylation of serine, threonine, and cysteine residues on proteolipids and acetylation to form N-acetyl neuraminic acid.

All tissues are capable of forming CoA from pantothenic acid, by the pathway shown in Figure 12.2 (Tahiliani and Beinlich, 1991; Begley et al., 2001). The first three enzymes catalyzing the formation ofphosphopantetheine from pantothenic acid are found only in the cytosol. Although phosphopanteth-eine crosses the mitochondrial inner membrane, CoA does not, but must be synthesized in situ.

The first step is phosphorylation to 4 -phosphopantothenic acid; the activity of pantothenate kinase is rate-limiting for CoA synthesis. There are two human genes for pantothenate kinase; genetic lack of the more recently discovered gene leads to an autosomal recessive neurodegenerative disease - the Hallevorden-Spatz syndrome. It is not clear how lack of pantothenate kinase leads to the accumulation of iron in the basal ganglia that is the underlying cause of the pathology (Zhou et al., 2001).

Pantothenol, the alcohol ofpantothenic acid (see Figure 12.1), is frequently used in pharmaceutical preparations. Although it is a substrate for pan-tothenate kinase in vitro, it is more likely that it first undergoes oxidation to pantothenic acid, catalyzed by liver alcohol dehydrogenase, rather than phos-phorylation to phosphopantothenol followed by oxidation.

Phosphopantothenic acid reacts with cysteine, forming 4 -phosphopant-othenyl cysteine, which is decarboxylated to 4 -phosphopantetheine in a flavin-dependent reaction. In most bacteria, phosphopantetheinyl cysteine synthase and decarboxylase occur as a single bifunctional enzyme, but the human enzymes occur as two separate proteins (Daugherty et al., 2002).

Phosphopantetheine undergoes adenylyl transfer from ATP to yield de-phospho-CoA, which is then phosphorylated at the 3' position of the ribose moiety to yield CoA. Phosphopantetheine adenylyltransferase and dephos-pho-CoA kinase activities occur in a single bifunctional enzyme, which is found in both cytosol and mitochondria. However, in addition to the bifunctional protein, human tissues also contain a separate dephospho-CoAkinase (Begley et al., 2001; Zhyvoloup et al., 2002). Metabolic Control of CoA Synthesis Pantothenate kinase is rate-limiting for the synthesis of CoA, and both regulation of the activity of the existing enzyme protein and changes in its synthesis are important in the control of intracellular concentrations of CoA (Rock et al., 2000). The enzyme has a low Km compared with the normal intracellular concentration of pantothenic acid and is thus insensitive to the availability of substrate, even in deficiency.

Short-chain fatty acyl CoA derivatives are inhibitors of pantothenate kinase; in perfused rat hearts, the addition of any of the major energy-yielding substrates (glucose, pyruvate, free fatty acids, or3-hydroxybutyrate) to the perfusion medium results in inhibition of pantothenate kinase and thus a reduced rate of CoA synthesis (Robishaw et al., 1982).

Expression of the pantothenate kinase gene is induced by glucagon (which is secreted under conditions when there is an increased need for CoA for fatty acid oxidation) and repressed by insulin (Kirschbaum et al., 1990; Yun et al., 2000).

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