A third MRX family (MRX68) is the result of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene: proposal of a rapid enzymatic assay for screening mentally retarded patients

Longo, Ilaria; Frints, Suzanna G.M.; Fryns, Jean‐Pierre; Meloni, Ilaria; Pescucci, Chiara; Ariani, Francesca; Borghgraef, Martine; Raynaud, Martine; Marynen, Peter; Schwartz, CE; Renieri, Alessandra; Froyen, Guido

doi:10.1136/jmg.40.1.11

Cited by 41 publications

(38 citation statements)

References 43 publications

(34 reference statements)

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“…Enzymatic activity of ACSL4 and the urinary creatine/creatinine ratio were measured as described previously. 5,6 Protein extraction and western blot analysis Cells from control and patient lymphoblastoid cell lines were lysed in buffer containing 48% urea, 15 mM Tris (pH 7.5), 8.7% glycerol, 1% SDS, 0.004% bromophenol blue and 143 mM b-mercaptoethanol. Western blot analysis was performed as previously described.…”

Section: Discussionmentioning

confidence: 99%

Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1

et al. 2011

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Section: Discussionmentioning

confidence: 99%

Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1

et al. 2011

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“…In human brain a longer splice variant is present and mutations are associated with a rare form of X-linked mental retardation [10,11]. The specific activity of rat ACSL4 is twice as high with arachidonate as with palmitate [9], and the apparent IC 50 of ACSL4 is ≤ 5 μM for 18:2, 18:3, 20:4, 22:5 and 22:6 with 16:0 as the labeled substrate [12].…”

Section: Introductionmentioning

confidence: 97%

Mutagenesis of rat acyl-CoA synthetase 4 indicates amino acids that contribute to fatty acid binding

Stinnett

Lewin

Coleman

2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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SummaryAlthough each of the five mammalian long-chain acyl-CoA synthetases (ACSL) can bind saturated and unsaturated fatty acids ranging from 12 to 22 carbons, ACSL4 prefers longer chain polyunsaturated fatty acids. In order to gain a better understanding of ACSL4 fatty acid binding, we based a mutagenesis approach on sequence alignments related to ttLC-FACS crystallized from Thermus thermophilus HB8. Four residues selected for mutagenesis corresponded to residues in ttLC-FACS that comprise the fatty acid binding pocket; the fifth residue aligned with a region thought to be involved in fatty acid selectivity of the Escherichia coli acyl-CoA synthetase, FadD. Changing an amino acid at the entry of the putative fatty acid binding pocket, G401L, resulted in an inactive enzyme. Mutating a residue near the pocket entry, L399M, did not significantly alter enzyme activity, but mutating a residue at the hydrophobic terminus of the pocket, S291Y, altered ACSL4's preference for 20:5 and 22:6 and increased its apparent Km for ATP. Mutating a site in a region previously identified as important for fatty acid binding also altered activation of 20:4 and 20:5. These studies suggested that the preference of ACSL4 for long-chain polyunsaturated fatty acids can be modified by altering specific amino acid residues.

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“…Despite the presence of other ACSL isoforms in brain, human ACSL4 is associated with depression [75] and mutations in the human Acsl4 gene that decrease 20:4-CoA synthetase activity cause a form of X-linked mental retardation [76][77][78]. The effect of these mutations suggests that ACSL4 is critical for normal brain function, perhaps related to its preference for long-chain polyunsaturated FAs [35], which are enriched in brain phospholipids.…”

Section: Acyl-coa Synthetases In Pathological Conditionsmentioning

confidence: 99%

“…Although the causality between the change of ACSL isoforms and specific diseases has not been established, these observations indicate that ACSL isoforms are linked to metabolic changes or FA demand under several pathological conditions. For example, in patients with inflammatory bowel disease, the increase of Acsl1 and Acsl4 mRNA in the terminal ileum and colon might provide acyl-CoAs for the synthesis of phospholipids; these can serve as precursors for inflammatory mediators or support membrane integrity of the affected intestine [74].Despite the presence of other ACSL isoforms in brain, human ACSL4 is associated with depression [75] and mutations in the human Acsl4 gene that decrease 20:4-CoA synthetase activity cause a form of X-linked mental retardation [76][77][78]. The effect of these mutations suggests that ACSL4 is critical for normal brain function, perhaps related to its preference for long-chain polyunsaturated FAs [35], which are enriched in brain phospholipids.…”

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confidence: 99%

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

2007

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Thirteen homologous proteins comprise the long-chain acyl-CoA synthetase (ACSL), fatty acid transport protein (FATP), and bubblegum (ACSBG) subfamilies that activate long-chain and verylong-chain fatty acids to form acyl-CoAs. Gain-and loss-of-function studies show marked differences in the ability of these enzymes to channel fatty acids into different pathways of complex lipid synthesis. Further, the ability of the ACSLs and FATPs to enhance cellular FA uptake does not always require these proteins to be present on the plasma membrane; instead, FA uptake can be increased by enhancing its conversion to acyl-CoA and its metabolism in downstream pathways. Since altered fatty acid metabolism is a hallmark of numerous metabolic diseases and pathological conditions, the ACSL, FATP and ACSBG isoforms are likely to play important roles in disease etiology. A family of acyl-CoA synthetases activates intracellular long-chain fatty acidsBefore a fatty acid (FA) from an exogenous or endogenous source can enter any metabolic pathway with the exception of eicosanoid metabolism, it must first be activated to form an acyl-CoA. This activation step is catalyzed by acyl-CoA synthetase (ACS) via a two-step reaction: 1) the formation of an intermediate fatty acyl-AMP with the release of pyrophosphate, and 2) the formation of a fatty acyl-CoA with the release of AMP.The ACS family is comprised of at least 25 members [1]. Although overlap exists, ACS family members are broadly classified by their substrate specificities for FAs of varying chain length. This review will focus on the three subfamilies of ACS enzymes that activate long-chain and/ or very-long-chain saturated and unsaturated FAs, long-chain ACSs (ACSL), very-long-chain ACSs (FATP), and bubblegum (ACSBG) isoforms [2].The ACSL, FATP and ACSBG families include multiple isoforms, each encoded by a separate gene (Tables 1, 2). Additionally, splice variants of ACSL isoforms have been identified in both humans and rodents [3]. ACS enzymes share significant amino acid sequence similarity, particularly in two highly conserved regions, a putative ATP-AMP signature motif for ATP binding and a motif for FA binding [4]. Despite these similarities, purified ACSL and FATP isoforms and their splice variants show distinct enzyme kinetics, differences in sensitivity to inhibitors ( Role of acyl-CoA synthetases in FA channelingThe existence of 13 ACSL, FATP and ACSBG isoforms that all activate long-chain FA has suggested that each has an independent role in channeling FA within cells. Unique roles for ACS isoforms were first identified in studies of Saccharomyces cerevisiae mutants that lacked the ACS isoforms Faa1 and Faa4, and were unable to use exogenously provided fatty acids [31]. Similarly, complementation studies of ACS-deficient E. coli showed that each of the 5 rat ACSL isoforms differs in its ability to channel FA into specific pathways like phospholipid synthesis and β-oxidation [32]. The ACSL and FATP isoforms also differ in their ability to complement FA uptake and a...

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A third MRX family (MRX68) is the result of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene: proposal of a rapid enzymatic assay for screening mentally retarded patients

Cited by 41 publications

References 43 publications

Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1

Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1

Mutagenesis of rat acyl-CoA synthetase 4 indicates amino acids that contribute to fatty acid binding

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

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