Isolation and functional expression of human <i>COQ2</i>, a gene encoding a polyprenyl transferase involved in the synthesis of CoQ

Forsgren, Margareta; Attersand, Anneli; Lake, Staffan; Grünler, Jacob; Świeżewska, Ewa; Dallner, Gustav; Climent, Isabel

doi:10.1042/bj20040261

Cited by 112 publications

(97 citation statements)

References 38 publications

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“…was also lower in these rescued cells compared with that of wild type (35). This could have been attributed to a lower activity in a foreign host, or perhaps the enzyme was sensitive to tail length.…”

Section: Discussionmentioning

confidence: 89%

Genetic Evidence for a Multi-subunit Complex in Coenzyme Q Biosynthesis in Yeast and the Role of the Coq1 Hexaprenyl Diphosphate Synthase

Gin

Clarke

2005

Journal of Biological Chemistry

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Coenzyme Q (Q) is a lipid that functions as an electron carrier in the mitochondrial respiratory chain in eukaryotes. There are eight complementation groups of Q-deficient Saccharomyces cerevisiae mutants designated coq1-coq8. Here we provide genetic evidence that several of the Coq polypeptides interact with one another. Deletions in any of the COQ genes affect the steady-state expression of Coq3p, Coq4p, and Coq6p. Antibodies that recognize Coq1p, a hexaprenyl diphosphate synthase, were generated and used to determine that Coq1p is peripherally associated with the inner membrane on the matrix side. Yeast ⌬coq1 mutants harboring diverse Coq1 orthologs from prokaryotic species produce distinct sizes of polyprenyl diphosphate and hence distinct isoforms of Q including Q 7 , Q 8 , Q 9 , or Q 10 (Okada, K., Kainou, T., Matsuda, H., and Kawamukai, M. (1998) FEBS Lett. 431, 241-244). We find that steady-state levels of Coq3p, Coq4p, and Coq6p are rescued in some cases to near wild-type levels by the presence of these diverse Coq1 orthologs in the ⌬coq1 mutant. These data suggest that the lipid product of Coq1p or a Q-intermediate derived from polyprenyl diphosphate is involved in stabilizing the Coq3, Coq4, and Coq6 polypeptides.

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Section: Discussionmentioning

confidence: 89%

Genetic Evidence for a Multi-subunit Complex in Coenzyme Q Biosynthesis in Yeast and the Role of the Coq1 Hexaprenyl Diphosphate Synthase

Gin

Clarke

2005

Journal of Biological Chemistry

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“…The OH-benzoate transpolyprenyltransferase (COQ2) gene encodes the enzyme involved in the second step of ubiquinone biosynthesis (13,22). In a second family with ubiquinone deficiency, a single base pair deletion was identified in the COQ2 gene, resulting in a premature stop codon and modifying the last 21 amino acids of the protein.…”

Section: Figurementioning

confidence: 99%

Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders

Mollet¹,

Giurgea²,

Schlemmer³

et al. 2007

J. Clin. Invest.

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232

219

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Coenzyme Q 10 (CoQ 10 ) plays a pivotal role in oxidative phosphorylation (OXPHOS), as it distributes electrons among the various dehydrogenases and the cytochrome segments of the respiratory chain. We have identified 2 novel inborn errors of CoQ 10 biosynthesis in 2 distinct families. In both cases, enzymologic studies showed that quinone-dependent OXPHOS activities were in the range of the lowest control values, while OXPHOS enzyme activities were normal. CoQ 10 deficiency was confirmed by restoration of normal OXPHOS activities after addition of quinone. A genome-wide search for homozygosity in family 1 identified a region of chromosome 10 encompassing the gene prenyldiphosphate synthase, subunit 1 (PDSS1), which encodes the human ortholog of the yeast COQ1 gene, a key enzyme of CoQ 10 synthesis. Sequencing of PDSS1 identified a homozygous nucleotide substitution modifying a conserved amino acid of the protein (D308E). In the second family, direct sequencing of OH-benzoate polyprenyltransferase (COQ2), the human ortholog of the yeast COQ2 gene, identified a single base pair frameshift deletion resulting in a premature stop codon (c.1198delT, N401fsX415). Transformation of yeast Δcoq1 and Δcoq2 strains by mutant yeast COQ1 and mutant human COQ2 genes, respectively, resulted in defective growth on respiratory medium, indicating that these mutations are indeed the cause of OXPHOS deficiency.

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“…20 -22 COQ2 is part of the CoQ 10 pathway and encodes the parahydroxybenzoate-polyprenyltransferase (EC 2.5.1.39), which catalyzes the prenylation of parahydroxybenzoate with a polyprenyl group. 2 Mutations in the COQ2 gene first were identified in two siblings with primary CoQ 10 deficiency, 8 and another child was recently reported. 23 One sibling of the former report presented with progressive encephalomyopathy and steroid-resistant nephrotic syndrome (NS), whereas his younger sister presented with isolated NS.…”

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confidence: 99%

COQ2 Nephropathy

Diomedi-Camassei

Giandomenico

Santorelli

et al. 2007

Journal of the American Society of Nephrology

310

260

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Primary coenzyme Q 10 (CoQ 10 ) deficiency includes a group of rare autosomal recessive disorders primarily characterized by neurological and muscular symptoms. Rarely, glomerular involvement has been reported. The COQ2 gene encodes the para-hydroxybenzoate-polyprenyl-transferase enzyme of the CoQ 10 synthesis pathway. We identified two patients with early-onset glomerular lesions that harbored mutations in the COQ2 gene. The first patient presented with steroid-resistant nephrotic syndrome at the age of 18 months as a result of collapsing glomerulopathy, with no extrarenal symptoms. The second patient presented at five days of life with oliguria, had severe extracapillary proliferation on renal biopsy, rapidly developed end-stage renal disease, and died at the age of 6 months after a course complicated by progressive epileptic encephalopathy. Ultrastructural examination of renal specimens from these cases, as well as from two previously reported patients, showed an increased number of dysmorphic mitochondria in glomerular cells. Biochemical analyses demonstrated decreased activities of respiratory chain complexes [IIϩIII] and decreased CoQ 10 concentrations in skeletal muscle and renal cortex. In conclusion, we suggest that inherited COQ2 mutations cause a primary glomerular disease with renal lesions that vary in severity and are not necessarily associated with neurological signs. COQ2 nephropathy should be suspected when electron microscopy shows an increased number of abnormal mitochondria in podocytes and other glomerular cells.

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Isolation and functional expression of human COQ2, a gene encoding a polyprenyl transferase involved in the synthesis of CoQ

Cited by 112 publications

References 38 publications

Genetic Evidence for a Multi-subunit Complex in Coenzyme Q Biosynthesis in Yeast and the Role of the Coq1 Hexaprenyl Diphosphate Synthase

Genetic Evidence for a Multi-subunit Complex in Coenzyme Q Biosynthesis in Yeast and the Role of the Coq1 Hexaprenyl Diphosphate Synthase

Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders

COQ2 Nephropathy

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