کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8261852 | 1534704 | 2010 | 5 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Carnitine palmitoyltransferase 2: New insights on the substrate specificity and implications for acylcarnitine profiling
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کلمات کلیدی
CPT2mitochondrial fatty acid β-oxidationVLCADLCHADDMHmFAOCPT1MTPcACTDMNLong-chain 3-hydroxyacyl-coA dehydrogenase - 3-hydroxyacyl-coA dehydrogenase طولانی زنجیره ایAcylcarnitine - آسیکارنیتینVery long-chain acyl-CoA dehydrogenase - آلی کلسیم دئودروژناز زنجیره بسیار طولانیMitochondrial trifunctional protein - پروتئین trifunctional میتوکندریcarnitine palmitoyltransferase 2 - کاردینیت پالمیتویل ترانسفراز 2Carnitine palmitoyltransferase 1 - کارنتین پالمیتویل ترانسفراز 1carnitine/acylcarnitine translocase - کارنیتین / آکیلکارینین پرولاکساز
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Over the last years acylcarnitines have emerged as important biomarkers for the diagnosis of mitochondrial fatty acid β-oxidation (mFAO) and branched-chain amino acid oxidation disorders assuming they reflect the potentially toxic acyl-CoA species, accumulating intramitochondrially upstream of the enzyme block. However, the origin of these intermediates still remains poorly understood. A possibility exists that carnitine palmitoyltransferase 2 (CPT2), member of the carnitine shuttle, is involved in the intramitochondrial synthesis of acylcarnitines from accumulated acyl-CoA metabolites. To address this issue, the substrate specificity profile of CPT2 was herein investigated. Saccharomyces cerevisiae homogenates expressing human CPT2 were incubated with saturated and unsaturated C2-C26 acyl-CoAs and branched-chain amino acid oxidation intermediates. The produced acylcarnitines were quantified by ESI-MS/MS. We show that CPT2 is active with medium (C8-C12) and long-chain (C14-C18) acyl-CoA esters, whereas virtually no activity was found with short- and very long-chain acyl-CoAs or with branched-chain amino acid oxidation intermediates. Trans-2-enoyl-CoA intermediates were also found to be poor substrates for CPT2. Inhibition studies performed revealed that trans-2-C16:1-CoA may act as a competitive inhibitor of CPT2 (Ki of 18.8 μM). The results obtained clearly demonstrate that CPT2 is able to reverse its physiological mechanism for medium and long-chain acyl-CoAs contributing to the abnormal acylcarnitines profiles characteristic of most mFAO disorders. The finding that trans-2-enoyl-CoAs are poorly handled by CPT2 may explain the absence of trans-2-enoyl-carnitines in the profiles of mitochondrial trifunctional protein deficient patients, the only defect where they accumulate, and the discrepancy between the clinical features of this and other long-chain mFAO disorders such as very long-chain acyl-CoA dehydrogenase deficiency.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1802, Issue 9, September 2010, Pages 728-732
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1802, Issue 9, September 2010, Pages 728-732
نویسندگان
Sara Violante, Lodewijk IJlst, Henk van Lenthe, Isabel Tavares de Almeida, Ronald J. Wanders, Fátima V. Ventura,