The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

Zammit, Victor A.

doi:10.1042/bj3430505

Cited by 89 publications

(68 citation statements)

References 143 publications

(161 reference statements)

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“…We showed recently that, in the heart, acetyl-CoA derived from the partial peroxisomal β-oxidation of long-chain and very-longchain fatty acids is used for malonyl-CoA synthesis [4], a key regulator of the mitochondrial oxidation of long-chain fatty acids [5,6]. This conclusion was based on the comparison of the 13 Clabelling of malonyl-CoA and the acetyl moiety of citrate, a proxy for mitochondrial acetyl-CoA [4].…”

Section: Introductionmentioning

confidence: 99%

Probing peroxisomal β-oxidation and the labelling of acetyl-CoA proxies with [1-13C]octanoate and [3-13C]octanoate in the perfused rat liver

Kasumov

Adams

Bian

et al. 2005

Biochemical Journal

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We reported previously that a substantial fraction of the acetyl groups used to synthesize malonyl-CoA in rat heart is derived from peroxisomal β-oxidation of long-chain and very-long-chain fatty acids. This conclusion was based on the interpretation of the 13 Clabelling ratio (malonyl-CoA)/(acetyl moiety of citrate) measured in the presence of substrates that label acetyl-CoA in mitochondria only (ratio < 1.0) or in both mitochondria and peroxisomes (ratio > 1.0). The goals of the present study were to test, in rat livers perfused with [1-13 C]octanoate or [3-13 C]octanoate, (i) whether peroxisomal β-oxidation contributes acetyl groups for malonylCoA synthesis, and (ii) the degree of labelling homogeneity of acetyl-CoA proxies (acetyl moiety of citrate, acetate, β-hydroxybutyrate, malonyl-CoA and acetylcarnitine). Our data show that (i) octanoate undergoes two cycles of peroxisomal β-oxidation in liver, (ii) acetyl groups formed in peroxisomes contribute to malonyl-CoA synthesis, (iii) the labelling of acetyl-CoA proxies is markedly heterogeneous, and (iv) the labelling of C1 + 2 of β-hydroxybutyrate does not reflect the labelling of acetyl-CoA used in the citric acid cycle.

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Section: Introductionmentioning

confidence: 99%

Probing peroxisomal β-oxidation and the labelling of acetyl-CoA proxies with [1-13C]octanoate and [3-13C]octanoate in the perfused rat liver

Kasumov

Adams

Bian

et al. 2005

Biochemical Journal

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“…Therefore, it is suggested that the interplay between the effects of the structural motifs on either side of the turn predicted for residues 15-19 (TPDG, see above) enables L-CPT I to respond to changes in the fluidity of the membrane in which TMs 1 and 2 are embedded, and with/ within which they are presumed to interact (7,11,22,27).…”

Section: Table II Comparison Of Activities and Kinetic Parameters Formentioning

confidence: 99%

Identification of Positive and Negative Determinants of Malonyl-CoA Sensitivity and Carnitine Affinity within the Amino Termini of Rat Liver- and Muscle-type Carnitine Palmitoyltransferase I

Jackson

Zammit

Price

2000

Journal of Biological Chemistry

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The extreme amino terminus and, in particular, residue Glu-3 in rat liver (L) carnitine palmitoyltransferase I (CPT I) have previously been shown to be essential for the sensitivity of the enzyme to inhibition by malonylCoA. Using the Pichia pastoris expression system, we now observe that, although mutants E3A (Glu-3 3 Ala) or ⌬(3-18) of L-CPT I have markedly lowered sensitivity to malonyl-CoA compared with the wild-type protein, the mutant ⌬(1-82) generated an enzyme that had regained much of the sensitivity of wild-type CPT I. This suggests that a region antagonistic to malonyl-CoA sensitivity is present within residues 19 -82 of the enzyme. This was confirmed in the construct ⌬(19 -30), which was found to be 50-fold more sensitive than wild-type L-CPT I. Indeed, this mutant was >4-fold more sensitive than even the native muscle (M)-CPT I isoform expressed and assayed under identical conditions. This behavior was dependent on the presence of Glu-3, with the mutant E3A-⌬(19 -30) having kinetic characteristics similar to those of the E3A mutant. The increase in the sensitivity of the L-CPT I-⌬(19 -30) mutant was not due to a change in the mechanism of inhibition with respect to palmitoyl-CoA, nor to any marked change of the K 0.5 for this substrate. Conversely, for M-CPT I, a decrease in malonyl-CoA sensitivity was invariably observed with increasing deletions from ⌬(3-18) to ⌬(1-80). However, deletion of residues 3-18 from M-CPT I affected the K m for carnitine of this isoform, but not of L-CPT I. These observations (i) provide the first evidence for negative determinants of malonyl-CoA sensitivity within the amino-terminal segment of L-CPT I and (ii) suggest a mechanism for the inverse relationship between affinity for malonyl-CoA and for carnitine of the two isoforms of the enzyme.Carnitine palmitoyltransferase I (CPT I, 1 malonyl-CoAsensitive) is an integral membrane protein first identified in the outer membrane and contact sites of mitochondria (1, 2). The enzyme catalyzes the formation of acylcarnitines from long-chain acyl-CoA esters, thus enabling the movement of acyl moieties across intracellular membranes. CPT I exists in two isoforms (Liver and Muscle), which have considerable sequence similarity but differ greatly, and inversely, in their malonyl-CoA sensitivity and K m for carnitine (3, 4). It is a polytopic protein, with two transmembrane (TM) segments and amino and carboxyl segments (approximately 46 and 652 residues, respectively) that are both exposed on the cytosolic aspect of the membrane (5). It has been shown that the extreme amino terminus of the nascent L-CPT I is retained in the mature protein (6) and, moreover, that it is essential for the expression of malonyl-CoA sensitivity (5, 7). Subsequent work with expressed CPT I constructs has confirmed these conclusions by showing that deletion of the amino-terminal highly conserved 6 amino acid residues of the L-isoform results in the loss of high affinity malonyl-CoA sensitivity (8). Glu-3, and to a much lesser extent His-5, have been identi...

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“…CPT-1 is an integral mitochondrial membrane protein that catalyzes the esterifcation of long-chain acyl-CoAs to L-carnitine, which is the rate-limiting step in the transport of these acyl moieties from the cytosol into the mitochondria, where they undergo fatty acid oxidation (20). CPT-1 is sensitive to inhibition by malonyl-CoA, which is important for signaling the availability of fuels (42), (43). In mammals, CPT-1 exists as two isoforms, liver and muscle (L-CPT-1 and M-CPT-1, respectively), that are similar in sequence but differ kinetically with respect to their malonyl-CoA sensitivities and K m values for carnitine (44), (45).…”

Section: C75 Inhibits Fas and Stimulates Cpt-1 And Fatty Acid Oxidatimentioning

confidence: 99%

C75, a Fatty Acid Synthase Inhibitor, Modulates AMP-activated Protein Kinase to Alter Neuronal Energy Metabolism

Landree¹,

Hanlon²,

Strong³

et al. 2004

Journal of Biological Chemistry

118

109

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C75, a synthetic inhibitor of fatty acid synthase (FAS), is hypothesized to alter the metabolism of neurons in the hypothalamus that regulate feeding behavior to contribute to the decreased food intake and profound weight loss seen with C75 treatment. In the present study, we characterize the suitability of primary cultures of cortical neurons for studies designed to investigate the consequences of C75 treatment and the alteration of fatty acid metabolism in neurons. We demonstrate that in primary cortical neurons, C75 inhibits FAS activity and stimulates carnitine palmitoyltransferase-1 (CPT-1), consistent with its effects in peripheral tissues. C75 alters neuronal ATP levels and AMP-activated protein kinase (AMPK) activity. Neuronal ATP levels are affected in a biphasic manner with C75 treatment, decreasing initially, followed by a prolonged increase above control levels. Cerulenin, a FAS inhibitor, causes a similar biphasic change in ATP levels, although levels do not exceed control. C75 and cerulenin modulate AMPK phosphorylation and activity. TOFA, an inhibitor of acetyl-CoA carboxylase, increases ATP levels, but does not affect AMPK activity. Several downstream pathways are affected by C75 treatment, including glucose metabolism and acetyl-CoA carboxylase (ACC) phosphorylation. These data demonstrate that C75 modulates the levels of energy intermediates, thus, affecting the energy sensor AMPK. Similar effects in hypothalamic neurons could form the basis for the effects of C75 on feeding behavior.Obesity has become a worldwide health issue, affecting children and adults in developed and emerging countries (1-3). Obesity is a disorder of both energy metabolism and appetite regulation and must be understood as a dysfunction of energy balance (3). The central nervous system (CNS) plays a critical role in the regulation of energy balance by coordinating peripheral and central signals to assess energy status and regulate feeding behavior (4 -6). While it is well known that fatty acid metabolism is an important component of the peripheral regulation of energy metabolism, recent studies indicate that neurons in the hypothalamus may monitor flux through the fatty acid synthesis pathway to ascertain energy balance (7-10).We and others have demonstrated that C75, a synthetic fatty acid synthase (FAS) 1 inhibitor (11), decreases food intake and results in profound and reversible weight loss (8,(12)(13)(14). Although inhibition of peripheral fatty acid synthesis might easily explain some of these effects, anorexia was also achieved by central (intracerebroventricular) administration of C75 (8, 14). These results suggest that the FAS pathway may play a role in energy homeostasis in the brain and that modulation of flux through this pathway in neurons or glia could alter energy levels.FAS is a lipogenic enzyme that catalyzes the condensation of acetyl-CoA and malonyl-CoA to generate long-chain fatty acids (15). In the fed state, long-chain fatty acids are synthesized and stored as triglycerides, which are broken down for...

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The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

Cited by 89 publications

References 143 publications

Probing peroxisomal β-oxidation and the labelling of acetyl-CoA proxies with [1-13C]octanoate and [3-13C]octanoate in the perfused rat liver

Probing peroxisomal β-oxidation and the labelling of acetyl-CoA proxies with [1-13C]octanoate and [3-13C]octanoate in the perfused rat liver

Identification of Positive and Negative Determinants of Malonyl-CoA Sensitivity and Carnitine Affinity within the Amino Termini of Rat Liver- and Muscle-type Carnitine Palmitoyltransferase I

C75, a Fatty Acid Synthase Inhibitor, Modulates AMP-activated Protein Kinase to Alter Neuronal Energy Metabolism

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