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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.
Carnitine transporter deficiency
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
The metabolism of fat begins with lipolysis; those patients with defective fatty acid oxidation have high ratios of free fatty acids to 3-hydroxybutyrate in blood after fasting. Once transported into cells, carnitine is esterified with acyl CoA esters, including those of fatty acids resulting from lipolysis. The esterifications are catalyzed by carnitine acyl transferases, such as carnitine palmitoyl transferase (CPT) I. Carnitine translocase then catalyzes the transfer of the fatty acylcarnitines across the membrane into the mitochondrion, where hydrolysis to fatty acyl CoA and free or recycled carnitine is catalyzed by CPT II. Fatty acyl CoA compounds then undergo β-oxidation in which there is successive shortening by two carbon atoms releasing acetyl CoA. In muscle, this is largely oxidized via the citric acid cycle, while in the liver ketogenesis proceeds via the successive action of 3-hydroxymethylglutaryl (HMG) CoA synthase and lyase-yielding acetoacetate, which is converted to 3-hydroxybutyrate.
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
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].
A cysteine trapping assay for risk assessment of reactive acyl CoA metabolites
Published in Xenobiotica, 2022
Nobuyuki Kakutani, Satoru Kobayashi, Toshio Taniguchi, Yukihiro Nomura
There are a number of commercially available drugs with carboxylic acid moieties. However, in some cases, drugs containing carboxylic acid can cause serious drug-induced liver injury (DILI) (Goldkind and Laine 2006). It is difficult to prove the mechanism, but it is believed that chemically reactive metabolites covalently bind to proteins and cause DILI (Lassila et al. 2015). Carboxylic acids are often subject to Phase II metabolic processes such as glucuronidation and amino acid conjugation. Acyl glucuronides are often detected, and the acyl migration peaks on the mass chromatograms are characteristic properties (Bailey and Dickinson 2003). The toxicity of acyl glucuronides is studied, and the chemical stability in phosphate buffer could influence the risk of acyl glucuronides (Sawamura et al. 2010). However, a quantitative risk assessment method for carboxylic acids and their detailed mechanisms of action are unclear. In addition to acyl glucuronides, acyl CoA metabolites are also considered notorious chemical species derived from carboxylic acids (Darnell and Weidolf 2013). Acyl CoA is formed by acyl CoA synthetases and subsequently conjugated by amino acids. The thioester of acyl CoA was more reactive than acyl glucuronide, and it easily reacted with proteins or was subject to hydrolysis (Grillo and Benet 2002). Despite the high interest, the reactivity and toxicity have not been studied compared with acyl glucuronides because acyl CoA cannot be detected in biological samples because of its high reactivity.