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Renata L S Goncalves, Victoria I Bunik, Martin D Brand
In humans, mutations in dehydrogenase E1 and transketolase domain containing 1 (DHTKD1) are associated with neurological abnormalities and accumulation of 2-oxoadipate, 2-aminoadipate, and reactive oxygen species. The protein encoded by DHTKD1 has sequence and structural similarities to 2-oxoglutarate dehydrogenase, and the 2-oxoglutarate dehydrogenase complex can produce superoxide/H2O2 at high rates. The DHTKD1 enzyme is hypothesized to catalyze the oxidative decarboxylation of 2-oxoadipate, a shared intermediate of the degradative pathways for tryptophan, lysine and hydroxylysine...
February 2016: Free Radical Biology & Medicine
Ashlee R Stiles, Leah Venturoni, Grace Mucci, Naser Elbalalesy, Michael Woontner, Stephen Goodman, Jose E Abdenur
2-Ketoadipic aciduria (OMIM 204750), a defect in the catabolic pathway of tryptophan, lysine, and hydroxylysine, is characterized by elevations in 2-ketoadipic, 2-aminoadipic, and 2-hydroxyadipic acids. Patients with the aforementioned biochemical profile have been described with a wide range of clinical presentations, from early-onset developmental delay, epilepsy, ataxia, and microcephaly to completely normal. This broad range of phenotypes has led some to question whether 2-ketoadipic aciduria represents a true disease state or if the biochemical abnormalities found in these patients merely reflect an ascertainment bias...
July 5, 2015: JIMD Reports
Jacob Hagen, Heleen te Brinke, Ronald J A Wanders, Alida C Knegt, Esmee Oussoren, A Jeannette M Hoogeboom, George J G Ruijter, Daniel Becker, Karl Otfried Schwab, Ingo Franke, Marinus Duran, Hans R Waterham, Jörn Oliver Sass, Sander M Houten
Alpha-aminoadipic and alpha-ketoadipic aciduria is an autosomal recessive inborn error of lysine, hydroxylysine, and tryptophan degradation. To date, DHTKD1 mutations have been reported in two alpha-aminoadipic and alpha-ketoadipic aciduria patients. We have now sequenced DHTKD1 in nine patients diagnosed with alpha-aminoadipic and alpha-ketoadipic aciduria as well as one patient with isolated alpha-aminoadipic aciduria, and identified causal mutations in eight. We report nine novel mutations, including three missense mutations, two nonsense mutations, two splice donor mutations, one duplication, and one deletion and insertion...
September 2015: Journal of Inherited Metabolic Disease
Yibo Wu, Evan G Williams, Sébastien Dubuis, Adrienne Mottis, Virginija Jovaisaite, Sander M Houten, Carmen A Argmann, Pouya Faridi, Witold Wolski, Zoltán Kutalik, Nicola Zamboni, Johan Auwerx, Ruedi Aebersold
The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study, we quantified the transcriptome--a subset of the metabolome--and, using targeted proteomics, quantified a subset of the liver proteome from 40 strains of the BXD mouse genetic reference population on two diverse diets. We discovered dozens of transcript, protein, and metabolite QTLs, several of which linked to metabolic phenotypes. Most prominently, Dhtkd1 was identified as a primary regulator of 2-aminoadipate, explaining variance in fasted glucose and diabetes status in both mice and humans...
September 11, 2014: Cell
Jonathan Baets, Peter De Jonghe, Vincent Timmerman
PURPOSE OF REVIEW: This article focuses on recent advances in Charcot-Marie-Tooth disease, in particular additions to the genetic spectrum, novel paradigms in molecular techniques and an update on therapeutic strategies. RECENT FINDINGS: Several new Charcot-Marie-Tooth disease-causing genes have been recently identified, further enlarging the genetic diversity and phenotypic variability, including: SBF1, DHTKD1, TFG, MARS, HARS, HINT1, TRIM1, AIFM1, PDK3 and GNB4...
October 2014: Current Opinion in Neurology
Jihyeon Lim, Zhongbo Liu, Pasha Apontes, Daorong Feng, Jeffrey E Pessin, Anthony A Sauve, Ruth H Angeletti, Yuling Chi
Chronic over-nutrition is a major contributor to the spread of obesity and its related metabolic disorders. Development of therapeutics has been slow compared to the speedy increase in occurrence of these metabolic disorders. We have identified a natural compound, mangiferin (MGF) (a predominant component of the plants of Anemarrhena asphodeloides and Mangifera indica), that can protect against high fat diet (HFD) induced obesity, hyperglycemia, insulin resistance and hyperlipidemia in mice. However, the molecular mechanisms whereby MGF exerts these beneficial effects are unknown...
2014: PloS One
Wangyang Xu, Houbao Zhu, Mingmin Gu, Qingqiong Luo, Jieying Ding, Yuting Yao, Fuxiang Chen, Zhugang Wang
Maintaining the functional integrity of mitochondria is crucial for cell function, signal transduction and overall cell activities. Mitochondrial dysfunctions may alter energy metabolism and in many cases are associated with neurological diseases. Recent studies have reported that mutations in dehydrogenase E1 and transketolase domain-containing 1 (DHTKD1), a mitochondrial protein encoding gene, could cause neurological abnormalities. However, the function of DHTKD1 in mitochondria remains unknown. Here, we report a strong correlation of DHTKD1 expression level with ATP production, revealing the fact that DHTKD1 plays a critical role in energy production in mitochondria...
November 1, 2013: FEBS Letters
Wang-Yang Xu, Ming-Min Gu, Lian-Hua Sun, Wen-Ting Guo, Hou-Bao Zhu, Jian-Fang Ma, Wen-Tao Yuan, Ying Kuang, Bao-Jun Ji, Xiao-Lin Wu, Yan Chen, Hong-Xin Zhang, Fu-Ting Sun, Wei Huang, Lei Huang, Sheng-di Chen, Zhu-Gang Wang
Charcot-Marie-Tooth (CMT) disease represents a clinically and genetically heterogeneous group of inherited neuropathies. Here, we report a five-generation family of eight affected individuals with CMT disease type 2, CMT2. Genome-wide linkage analysis showed that the disease phenotype is closely linked to chromosomal region 10p13-14, which spans 5.41 Mb between D10S585 and D10S1477. DNA-sequencing analysis revealed a nonsense mutation, c.1455T>G (p.Tyr485(∗)), in exon 8 of dehydrogenase E1 and transketolase domain-containing 1 (DHTKD1) in all eight affected individuals, but not in other unaffected individuals in this family or in 250 unrelated normal persons...
December 7, 2012: American Journal of Human Genetics
Katharina Danhauser, Sven W Sauer, Tobias B Haack, Thomas Wieland, Christian Staufner, Elisabeth Graf, Johannes Zschocke, Tim M Strom, Thorsten Traub, Jürgen G Okun, Thomas Meitinger, Georg F Hoffmann, Holger Prokisch, Stefan Kölker
Abnormalities in metabolite profiles are valuable indicators of underlying pathologic conditions at the molecular level. However, their interpretation relies on detailed knowledge of the pathways, enzymes, and genes involved. Identification and characterization of their physiological function are therefore crucial for our understanding of human disease: they can provide guidance for therapeutic intervention and help us to identify suitable biomarkers for monitoring associated disorders. We studied two individuals with 2-aminoadipic and 2-oxoadipic aciduria, a metabolic condition that is still unresolved at the molecular level...
December 7, 2012: American Journal of Human Genetics
Victoria I Bunik, Dmitry Degtyarev
Structural relationship within the family of the thiamine diphosphate-dependent 2-oxo acid dehydrogenases was analyzed by combining different methods of sequence alignment with crystallographic and enzymological studies of the family members. For the first time, the sequence similarity of the homodimeric 2-oxoglutarate dehydrogenase to heterotetrameric 2-oxo acid dehydrogenases is established. The presented alignment of the catalytic domains of the dehydrogenases of pyruvate, branched-chain 2-oxo acids and 2-oxoglutarate unravels the sequence markers of the substrate specificity and the essential residues of the family members without the 3D structures resolved...
May 1, 2008: Proteins
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