A structural mapping of mutations causing succinyl‐CoA:3‐ketoacid CoA transferase (SCOT) deficiency

Shafqat, N.; Kavanagh, K.L.; Sass, Jörn Oliver; Christensen, Ernst; Fukao, Toshiyuki; Lee, Wen‐Hwa; Oppermann, U.; Yue, Wyatt W.

doi:10.1007/s10545-013-9589-z

Cited by 26 publications

(22 citation statements)

References 24 publications

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“…This reaction is the first and rate-limiting step of ketone body utilization in peripheral tissues. By transferring CoA moiety from succinyl-CoA to form acetoacetyl-CoA, the entry of acetoacetate into the TCA cycle becomes possible and it can be used for energy production [207].…”

Section: Inherited Diseases In Which Ketosis Occursmentioning

confidence: 99%

Breath acetone as a potential marker in clinical practice

Ruzsányi

Kalapos²

2017

J. Breath Res.

133

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In recent decades, two facts have changed the opinion of researchers about the function of acetone in humans. Firstly, it has turned out that acetone cannot be regarded as simply a waste product of metabolism, because there are several pathways in which acetone is produced or broken down. Secondly, methods have emerged making possible its detection in exhaled breath, thereby offering an attractive alternative to investigation of blood and urine samples. From a clinical point of view the measurement of breath acetone levels is important, but there are limitations to its wide application. These limitations can be divided into two classes, technical and biological limits. The technical limits include the storage of samples, detection threshold, standardization of clinical settings, and the price of instruments. When considering the biological ranges of acetone, personal factors such as race, age, gender, weight, food consumption, medication, illicit drugs, and even profession/class have to be taken into account to use concentration information for disorders. In some diseases such as diabetes mellitus and lung cancer, as well as in nutrition-related behavior such as starvation and ketogenic diet, breath acetone has been extensively examined. At the same time, there is a lack of investigations in other cases in which ketosis is also evident, such as in alcoholism or an inborn error of metabolism. In summary, the detection of acetone in exhaled breath is a useful and promising tool for diagnosis and it can be used as a marker to follow the effectiveness of treatments in some disorders. However, further endeavors are needed for clarification of the exact distribution of acetone in different body compartments and evaluation of its complex role in humans, especially in those cases in which a ketotic state also occurs. RECEIVED

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Section: Inherited Diseases In Which Ketosis Occursmentioning

confidence: 99%

Breath acetone as a potential marker in clinical practice

Ruzsányi

Kalapos²

2017

J. Breath Res.

133

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“…Most KB metabolism occurs in the mitochondria and is catalyzed by the enzymes 3‐hydroxybutyrate dehydrogenase, type 1 (BDH1), succinyl‐CoA:3‐ketoacid‐coenzyme A transferase 1 (OXCT1), and acetyl‐CoA acetyltransferase 1 (ACAT1) (2). Mutations of genes encoding these enzymes are associated with exacerbated ketosis in humans (3). Moreover, knockout of the rate‐limiting ketolytic enzyme OXCT1 leads to severe hyperketonemia and lethality in mice (4).…”

mentioning

confidence: 99%

Skeletal muscle PGC‐1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice

et al. 2016

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Ketone bodies (KBs) are crucial energy substrates during states of low carbohydrate availability. However, an aberrant regulation of KB homeostasis can lead to complications such as diabetic ketoacidosis. Exercise and diabetes affect systemic KB homeostasis, but the regulation of KB metabolism is still enigmatic. In our study in mice with either knockout or overexpression of the peroxisome proliferator-activated receptor-g coactivator (PGC)-1a in skeletal muscle, PGC-1a regulated ketolytic gene transcription in muscle. Furthermore, KB homeostasis of these mice was investigated during withholding of food, exercise, and ketogenic diet feeding, and after streptozotocin injection. In response to these ketogenic stimuli, modulation of PGC-1a levels in muscle affected systemic KB homeostasis. Moreover, the data demonstrate that skeletal muscle PGC-1a is necessary for the enhanced ketolytic capacity in response to exercise training and overexpression of PGC-1a in muscle enhances systemic ketolytic capacity and is sufficient to ameliorate diabetic hyperketonemia in mice. In cultured myotubes, the transcription factor estrogen-related receptor-a was a partner of PGC-1a in the regulation of ketolytic gene transcription. These results demonstrate a central role of skeletal muscle PGC-1a in the transcriptional regulation of systemic ketolytic capacity.-Svensson, K., Albert, V., Cardel, B., Salatino, S., Handschin, C. Skeletal muscle PGC-1a modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice. FASEB J. 30, 1976FASEB J. 30, -1986FASEB J. 30, (2016 During prolonged starvation, when carbohydrate availability is low, the ketone bodies (KBs) b-hydroxybutyrate (bOHB) and acetoacetate (AcAc) are necessary metabolic fuels that help maintain energy homeostasis (1). KBs are produced in the liver and are subsequently metabolized to acetyl-CoA in extrahepatic organs. Most KB metabolism occurs in the mitochondria and is catalyzed by the enzymes 3-hydroxybutyrate dehydrogenase, type 1 (BDH1), succinyl-CoA:3-ketoacid-coenzyme A transferase 1 (OXCT1), and acetyl-CoA acetyltransferase 1 (ACAT1) (2). Mutations of genes encoding these enzymes are associated with exacerbated ketosis in humans (3). Moreover, knockout of the rate-limiting ketolytic enzyme OXCT1 leads to severe hyperketonemia and lethality in mice (4). Hyperketonemia is a common complication in diabetes that can lead to severe and possibly lethal ketoacidosis (5) and has been attributed in part to impaired peripheral KB oxidation (6). However, relatively little is known about the transcriptional regulation of ketolytic enzymes (7). The peroxisome proliferator-activated receptor g coactivator (PGC)-1a is an essential transcriptional coactivator and has a well-established role in the regulation of mitochondrial metabolic processes such as oxidative phosphorylation and the tricarboxylic acid (TCA) cycle (8). Although these metabolic pathways are crucial for complete oxidation of KBs, it is not known whether PGC-1a directly affects the ...

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“…This point mutation had previously been classified as a variant of unknown significance in three individuals in 2014. 31 Our patient's presentation presents compelling evidence for pathogenicity of 32 Based on this paper and structure analysis using Chimera molecular modeling system (University of California, San Francisco), it appears that our patient's mutated residue falls in close proximity to known pathogenic mutations in a highly conserved hydrophobic pocket important for protein dimerization. 32,33 Introduction of a larger but still hydrophobic residue would likely inhibit but not eliminate SCOT dimerization, providing a theoretical mechanism for protein dysfunction in this case.…”

Section: Discussionmentioning

confidence: 87%

A Case of Succinyl-CoA:3-Oxoacid CoA Transferase Deficiency Presenting with Severe Acidosis in a 14-Month-Old Female: Evidence for Pathogenicity of a Point Mutation in the OXCT1 Gene

Zheng

Hooper

Spencer‐Manzon

et al. 2017

J Pediatr Intensive Care

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We describe a case of succinyl-CoA:3-oxoacid CoA transferase (SCOT) deficiency in an otherwise healthy 14 month-old female. She presented with lethargy, tachypnea, and hyperpnea with hypoglycemia and a severe anion gap metabolic acidosis. Early management included correction of the acidosis and metabolic support with dextrose and insulin. Inborn errors of metabolism are rare outside the neonatal period. However, SCOT deficiency may present at older ages. Maintaining a high index of suspicion, immediate transfer to a pediatric intensive care unit, and prompt metabolic support are key to achieving a favorable outcome.

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A structural mapping of mutations causing succinyl‐CoA:3‐ketoacid CoA transferase (SCOT) deficiency

Cited by 26 publications

References 24 publications

Breath acetone as a potential marker in clinical practice

Breath acetone as a potential marker in clinical practice

Skeletal muscle PGC‐1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice

A Case of Succinyl-CoA:3-Oxoacid CoA Transferase Deficiency Presenting with Severe Acidosis in a 14-Month-Old Female: Evidence for Pathogenicity of a Point Mutation in the OXCT1 Gene

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