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Carrier Screening For Inherited Genetic Conditions
Published in Vincenzo Berghella, Obstetric Evidence Based Guidelines, 2022
Whitney Bender, Lorraine Dugoff
Clinical features: This disorder is caused by a deficiency of medium-chain acyl-CoA dehydrogenase. This disorder is characterized by an intolerance to prolonged fasting, recurrent episodes of hypoglycemic coma, impaired ketogenesis, and low plasma and tissue carnitine levels.
Metabolism
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
The combustion of fatty acids, the major energy component of fats, commences with their activation to CoA derivatives such as palmitoyl CoA. Palmitoyl CoA must be first converted to palmitoylcarnitine by carnitine-palmitoyltransferase in the outer mitochondrial membrane before it can enter the mitochondrion. At the inner mitochondrial membrane, palmitoyl carnitine is reconverted to palmitoyl CoA and then oxidized by β-oxidation, which releases two carbon compounds as acetyl CoA until the entire fatty acid molecule is broken down. β-Oxidation of free fatty acids provides a major source of acetyl CoA, an important substrate for the citric acid cycle. Free fatty acids in blood, derived from the diet or by the action of lipoprotein lipase on lipoproteins at the endothelial cell layer of tissue, are oxidized in the mitochondria. Growth hormone and glucocorticoid increase the mobilization of fat stores by increasing the amount of triglyceride lipase. Initially, free fatty acid is converted to acyl CoA utilizing one ATP. Acyl CoA is oxidized to acetyl CoA, and the residual carbon atoms re-enter the cycle to produce more acetyl CoA (Figure 65.6). This partial oxidation of free fatty acids produces hydrogen ions that are removed as NADH and reduced flavoproteins.
Introduction to disorders of fatty acid oxidation
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Specific acylCoA dehydrogenases (ACADs) with overlapping specificities for chain length include: short-chain acyl CoA dehydrogenase (SCAD) (Chapter 42), medium-chain acyl CoA dehydrogenase (MCAD) (Chapter 39), and very long-chain acyl CoA dehydrogenase (VLCAD) (Chapter 40). In addition, a tri-functional enzyme catalyzes 3-hydroxyacyl dehydrogenation, 2-enoyl-CoA hydration, and 3-oxoacylCoA thiolysis [7]. Long-chain hydroxyacyl CoA dehydrogenase (LCHAD) is now known to be one of these three enzymatic steps of the tri-functional protein (Chapter 41).
Myeloid neoplasm with ETV6::ACSl6 fusion: landscape of molecular and clinical features
Published in Hematology, 2022
Zhan Su, Xin Liu, Weiyu Hu, Jie Yang, Xiangcong Yin, Fang Hou, Yaqi Wang, Jinglian Zhang
The ETS variant 6 gene (ETV6), mapping to chromosome 12p13.2, belongs to the E-twenty-six (ETS) family of transcription factors. As a transcriptional repressor, ETV6 binds to the 5'-CCGGAAGT-3’ DNA sequence via its C-terminal DNA-binding domain and exerts functions in association with a plethora of corepressors, i.e. SIN3A, NCOR, and HDAC3. ETV6 is ubiquitously expressed in a broad spectrum of tissues, including bone marrow. ETV6 is essential for maintaining hematopoietic stem cell function and megakaryocyte development [15, 16]. A variety of ETV6 germline or somatic aberrations have been reported in hematologic malignancies, such as mutations, deletions, rearrangements, and fusions, demonstrating its role in leukemogenesis [17, 18]. Acyl-CoA synthetase long chain family member 6 (ACSL6) belongs to the long-chain acyl-CoA synthetase (ACSL) family. ACSL6 catalyzes the conversion of long-chain fatty acids to their active form, acyl-CoA, together with CoA and ATP. ACSL6 is essential for fatty acid metabolism and affects mitochondrial content, respiratory rates, and lipid oxidation. ACSL6 is highly expressed in the brain, testis, and bone marrow, and it has been found to be related to cell proliferation and apoptosis [19–22].
Immunostimulatory effects of vitamin B5 improve anticancer immunotherapy
Published in OncoImmunology, 2022
Melanie Bourgin, Oliver Kepp, Guido Kroemer
Vitamin B5 (pantothenic acid) has recently joined the club of immunostimulatory B vitamins. Vitamin B5 is a precursor of coenzyme A (CoA), an essential cofactor for energy metabolism and fatty acid oxidation.20 CoA can be conjugated to acetate to form acetyl-CoA thioester, which plays a central role in the intersection between amino acid catabolism, glycolysis, fatty acid metabolism, as well as a donor of acetyl groups for acetylation reactions,21 and longer acyl-CoA derivatives, which serve as “activated” fatty acids to participate in intracellular fatty acid transport and lipid biosynthesis.22,23 Of note, a protective effect has been ascribed to vitamin B5 in the context of infection by Plasmodium falciparum, the pathogen responsible for malaria.24 Similarly, vitamin B5 supplementation of mice can afford protection against Mycobacterium tuberculosis, the infectious agent causing tuberculosis, through improved T cell-mediated immunity.25
A cysteine trapping assay for risk assessment of reactive acyl CoA metabolites
Published in Xenobiotica, 2022
Nobuyuki Kakutani, Satoru Kobayashi, Toshio Taniguchi, Yukihiro Nomura
To increase the sensitivity of the assay, the supplements for the acyl CoA metabolic assay were investigated. The addition of DTT dramatically increased the sensitivity of the assay for acyl CoA metabolites and Cys conjugates. It is considered that DTT helped the thiol moieties of Cys and CoA maintain their reduced forms, which are required for the nucleophilic reaction. Triton X-100 was added, and its effect was compared with that of the pore-forming peptide alamethicin. Triton X-100 increased the metabolic activity of acyl CoA, whereas alamethicin had no such effect (Figure 4). The DMSO concentration did not affect the assay results up to at least 1% in these conditions (Supplement Figure 1). When lysine was used instead of cysteine, the corresponding conjugates were detected in only trace amounts (Supplement Figure 2).