Combined enzyme defect of mitochondrial fatty acid oxidation.

Jackson, Sandra; Kler, Rajinder Singh; Bartlett, K.; Briggs, Helen L.; Bindoff, Laurence A.; Pourfarzam, Morteza; Gardner-Medwin, D.; Turnbull, D. M.

doi:10.1172/jci115983

Cited by 123 publications

(63 citation statements)

References 24 publications

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“…The 3-hydroxyacyl-CoA dehydrogenase measured with acetoacetyl-CoA was normal. These results establish a mitochondrial trifunctional protein (MTP) deÐciency in this family which so far has been described in its early lethal and a later-manifesting form in 4 patients (Jackson et al 1992 ;Wanders et al 1992 ;Dionisi-Vici et al 1996).…”

supporting

confidence: 56%

Neonatal lethal mitochondrial trifunctional protein deficiency mimicking a respiratory chain defect

Grünewald

Bakkeren

Wanders

et al. 1997

J of Inher Metab Disea

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supporting

confidence: 56%

Neonatal lethal mitochondrial trifunctional protein deficiency mimicking a respiratory chain defect

Grünewald

Bakkeren

Wanders

et al. 1997

J of Inher Metab Disea

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“…Two forms of trifunctional protein deficiency have been described (5,6). In the less common form, marked reduction in the amount of both a and , subunits is present by immunoanalysis and all three enzymatic activities are reduced.…”

Section: Discussionmentioning

confidence: 99%

“…The a subunit contains the long chain enoyl-CoA hydratase and LCHAD activities. Using immunologic and biochemical techniques, two groups (5,6) proved that LCHAD deficiency has two different biochemical phenotypes. The first includes deficiency of all three enzyme activities of the trifunctional protein, with loss of both a and 1 subunits by immunoblotting studies.…”

mentioning

confidence: 99%

The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy.

Sims

Brackett

Powell

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

203

112

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Mitochondrial long chain fatty acid 13-oxidation provides the major source of energy in the heart. Deficiencies of human 13-oxidation enzymes produce sudden, unexplained death in childhood, acute hepatic encephalopathy, skeletal myopathy, or cardiomyopathy. Long chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NAD+ oxidoreductase, EC 1.1.1.211] catalyzes the third step in 13-oxidation, and this activity is present on the C-terminal portion of the a subunit of mitochondrial trifunctional protein. We used single-stranded conformation variance analysis of the exons of the human LCHAD (et subunit) gene to determine the molecular basis of LCHAD deficiency in three families with children presenting with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all families, the mothers had acute fatty liver and associated severe complications during pregnancies with the affected infants. The analysis in two affected children revealed a G to C mutation at position 1528 (G1528C) of the a subunit of the trifunctional protein on both alleles. This is in the LCHAD domain and substitutes glutamine for glutamic acid at position 474 of mature a subunit. The third child had this G1528C mutation on one allele and a different mutation (C1132T) creating a premature termination codon (residue 342) on the second allele. Our results demonstrate that mutations in the LCHAD domain of the trifunctional protein a subunit in affected offspring are associated with maternal acute fatty liver of pregnancy. This is the initial delineation of the molecular basis of isolated LCHAD deficiency.Long chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NADI oxidoreductase, EC 1.1.1.211] activity catalyzes the third step in the mitochondrial (3-oxidation spiral. (3-Oxidation provides the major source of energy in heart and skeletal muscle and is essential for intermediary metabolism in the liver. The (3-oxidation of long chain fatty acids requires four sequential enzyme activities: the initial fatty acyl-CoA dehydrogenase, a 2,3-enoyl-CoA hydratase, a 3-hydroxyacyl-CoA dehydrogenation step, and a 3-ketoacyl-CoA thiolase. With each cycle through the spiral, the long chain fatty acid substrate is reduced by two carbons, producing acetyl CoA. Because of the range of fatty acid substrate lengths, each of these reactions is catalyzed by two to four separate enzymes encoded by individual nuclear genes and with differing substrate specificities.

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“…Hence there seems to be important inter-tissue variation in the control of mitochondria1 P-oxidation. It is also interesting to note that there seems to be variation in human tissues; control human skeletal-muscle (Jackson et al, 1992), heart (Eaton, 1992) and fibroblast (Singh Kler et al, 1991) mitochondria produce only saturated intermediates, whereas human liver mitochondria produce significant levels of 2-enoyl-CoA and 3-hydroxyacyl-CoA intermediates (Eaton et al, 1993b).…”

Section: Discussionmentioning

confidence: 99%

Redox control of β‐oxidation in rat liver mitochondria

Eaton

Turnbull

Bartlett

1994

European Journal of Biochemistry

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Coupled rat liver mitochondria were incubated with [U-i4C]hexadecanoate and carnitine which resulted in the formation of acyl-, 2-enoyl-and 3-hydroxyacyl-CoA and carnitine esters. The production of 2-enoyl-CoA and 3-hydroxyacyl-CoA esters was associated with a significant lowering of the NAD'NADH ratio, in contrast to rat muscle mitochondria [Eaton, S., Bhuiyan, A. K. M. J., Kler, R. S., Turnbull, D. M. & Bartlett, K. (1993) Biochem. J. 289, 161-1721, suggesting that control by the respiratory chain is important under normal conditions. When NAD'NADH ratios were held low by succinate-induced reverse electron flow, 3-enoyl-CoA esters were also detected, probably formed by the action of 3,2-enoyl-CoA isomerase. Measurement of the flux of P-oxidation at different osmolalities showed that flux was strongly dependent on osmolality changes in the physiological range. Measurement of the CoA and carnitine esters resulting from incubations made at different osmolalities showed that there was an increase in the amounts of the saturated acyl-CoA esters with respect to 2-enoyl-CoA and 3-hydroxyacyl-CoA esters, consistent with control by the electron-transfer flavoprotein-ubiquinone segment [Halestrap, A. P. & Dunlop, J. L. (1986) Biochem. J. 239, 559-5651. This however could not be the only factor operating as indicated by the continued presence of 2-enoyl-CoA and 3-hydroxyacyl-CoA esters at high osmolalities.Mitochondria1 P-oxidation is linked to the respiratory chain at two stages ; the 3-hydroxyacyl-CoA dehydrogenases to complex I via NAD'DJADH and the acyl-CoA dehydrogenases to ubiquinone via electron-transfer flavoprotein (ETF) and its oxidoreductase (ETF: QO). Inhibition of respiratory-chain activity at the level of complex I leads to diminished P-oxidation flux and the accumulation of 3-hydroxyacyl-CoA and 2-enoyl-CoA and carnitine esters (Bremer and

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Combined enzyme defect of mitochondrial fatty acid oxidation.

Cited by 123 publications

References 24 publications

Neonatal lethal mitochondrial trifunctional protein deficiency mimicking a respiratory chain defect

Neonatal lethal mitochondrial trifunctional protein deficiency mimicking a respiratory chain defect

The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy.

Redox control of β‐oxidation in rat liver mitochondria

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