Sterol Biosynthesis

Schroepfer, George J.

doi:10.1146/annurev.bi.50.070181.003101

Cited by 225 publications

(98 citation statements)

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“…In the mevalonate shunt first proposed in 1974 by Edmond and Popjak (7), dimethylallyl pyrophosphate is dephosphorylated to the free alcohol, oxidized in two steps to 3-methylcrotonic acid, and then activated with CoA to form 3-methylcrotonylCoA, the precursor of 3MGC-CoA in the normal leucine catabolic pathway. Other plausible links between the two pathways at the level of higher order isoprenoids, such as geraniol and farnesol , have been described by Schroepfer (8). Also possible is formation of 3MGC-CoA by dehydration of HMG-CoA , either spontaneously or by reverse activity of 3MGC-CoA hydratase.…”

mentioning

confidence: 88%

3-Methylglutaconic Acidemia in Smith-Lemli-Opitz Syndrome

Kelley

Kratz

1995

Pediatr Res

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confidence: 88%

3-Methylglutaconic Acidemia in Smith-Lemli-Opitz Syndrome

Kelley

Kratz

1995

Pediatr Res

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“…E. histolytica lacks several enzymes for the classical sterol 6 biosynthesis pathway (Schroepfer, 1981 The genome contains five putative prenyl transferase genes, which all have 8 been annotated as geranylgeranyl-diphosphate synthases. Their sequences are 9 highly similar, with the exception that the open reading frames are disrupted in 10 two of them (XP_650479 and XP_655958).…”

Section: Tryptophanmentioning

confidence: 99%

Structure and Content of the Entamoeba histolytica Genome

Clark

Tazreiter

et al. 2007

Advances in Parasitology

175

166

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“…As a result, MGC measurements can serve as a proxy for both MGC and MGR. Although the best documented origin of MGC in human metabolism is from mitochondrial 3-methylglutaconyl-CoA, Edmond and Popjak (Edmond and Popjak, 1974) and Schroepfer (Schroepfer, 1981) proposed and/or showed evidence for several extra-mitochondrial sources of MGC, all of which derive ultimately from 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA; Fig. 1B) (Landau and Brunengraber, 1985;Poston, 1976).…”

Section: Introductionmentioning

confidence: 99%

A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3

et al. 2010

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SUMMARYCosteff Syndrome, which is caused by mutations in the OPTIC ATROPHY 3 (OPA3) gene, is an early-onset syndrome characterized by urinary excretion of 3-methylglutaconic acid (MGC), optic atrophy and movement disorders, including ataxia and extrapyramidal dysfunction. The OPA3 protein is enriched in the inner mitochondrial membrane and has mitochondrial targeting signals, but a requirement for mitochondrial localization has not been demonstrated. We find zebrafish opa3 mRNA to be expressed in the optic nerve and retinal layers, the counterparts of which in humans have high mitochondrial activity. Transcripts of zebrafish opa3 are also expressed in the embryonic brain, inner ear, heart, liver, intestine and swim bladder. We isolated a zebrafish opa3 null allele for which homozygous mutants display increased MGC levels, optic nerve deficits, ataxia and an extrapyramidal movement disorder. This correspondence of metabolic, ophthalmologic and movement abnormalities between humans and zebrafish demonstrates a phylogenetic conservation of OPA3 function. We also find that delivery of exogenous Opa3 can reduce increased MGC levels in opa3 mutants, and this reduction requires the mitochondrial localization signals of Opa3. By manipulating MGC precursor availability, we infer that elevated MGC in opa3 mutants derives from extra-mitochondrial HMGCoA through a non-canonical pathway. The opa3 mutants have normal mitochondrial oxidative phosphorylation profiles, but are nonetheless sensitive to inhibitors of the electron transport chain, which supports clinical recommendations that individuals with Costeff Syndrome avoid mitochondria-damaging agents. In summary, this paper introduces a faithful Costeff Syndrome model and demonstrates a requirement for mitochondrial OPA3 to limit HMG-CoA-derived MGC and protect the electron transport chain against inhibitory compounds.

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Sterol Biosynthesis

Cited by 225 publications

References 0 publications

3-Methylglutaconic Acidemia in Smith-Lemli-Opitz Syndrome

3-Methylglutaconic Acidemia in Smith-Lemli-Opitz Syndrome

Structure and Content of the Entamoeba histolytica Genome

A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3

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