Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Organisms, which grow on organic substrates that are metabolized via acetyl-CoA, are faced with the problem to form all cell constituents from this C(2)-unit. The problem was solved by the seminal work of Kornberg and is known as the glyoxylate cycle. However, many bacteria are known to not contain isocitrate lyase, the key enzyme of this pathway. This problem was addressed in acetate-grown Rhodobacter sphaeroides. An acetate-minus mutant identified by transposon mutagenesis was affected in the gene for beta-ketothiolase forming acetoacetyl-CoA from two molecules of acetyl-CoA. This enzyme activity was missing in this mutant, which grew on acetoacetate and on acetate plus glyoxylate. A second acetate/acetoacetate-minus mutant was affected in the gene for a putative mesaconyl-CoA hydratase, an enzyme which catalyses the hydration of mesaconyl-CoA to beta-methylmalyl-CoA. Beta-methylmalyl-CoA is further cleaved into glyoxylate and propionyl-CoA. These results as well as identification of acetate-upregulated proteins by two-dimensional gel electrophoresis lead to the proposal of a new pathway for acetate assimilation. In a first part, affected by the mutations, two molecules of acetyl-CoA and one molecule CO(2) are converted via acetoacetyl-CoA and mesaconyl-CoA to glyoxylate and propionyl-CoA. In a second part glyoxylate and propionyl-CoA are converted with another molecule of acetyl-CoA and CO(2) to l-malyl-CoA and succinyl-CoA.
Mol Microbiol 2006 Jul
PMID:Study of an alternate glyoxylate cycle for acetate assimilation by Rhodobacter sphaeroides. 1685 35

Using the metabolomics-guided screening coupled to N-ethyl-N-nitrosourea-mediated mutagenesis, we identified mice that exhibited elevated levels of long-chain acylcarnitines. Whole genome homozygosity mapping with 262 SNP markers mapped the disease gene to chromosome 5 where candidate genes Hadha and Hadhb, encoding the mitochondria trifunctional protein (MTP) alpha- and beta-subunits, respectively, are located. Direct sequencing revealed a normal alpha-subunit, but detected a nucleotide T-to-A transversion in exon 14 (c.1210T>A) of beta-subunit (Hadhb) which resulted in a missense mutation of methionine to lysine (M404K). Western blot analysis showed a significant reduction of both the alpha- and beta-subunits, consistent with reduced enzyme activity in both the long-chain 3-hydroxyacyl-CoA dehydrogenase and the long-chain 3-ketoacyl-CoA thiolase activities. These mice had a decreased weight gain and cardiac arrhythmias which manifested from a prolonged PR interval to a complete atrio-ventricular dissociation, and died suddenly between 9 and 16 months of age. Histopathological studies showed multifocal cardiac fibrosis and hepatic steatosis. This mouse model will be useful to further investigate the mechanisms underlying arrhythmogenesis relating to lipotoxic cardiomyopathy and to investigate pathophysiology and treatment strategies for human MTP deficiency.
Hum Mol Genet 2006 Dec 15
PMID:ENU mutagenesis identifies mice with cardiac fibrosis and hepatic steatosis caused by a mutation in the mitochondrial trifunctional protein beta-subunit. 1711 38

The transcriptome pattern of metabolic genes in vitamin A deficient (VAD) liver has been compared to the vitamin A-sufficient (VAS) state using the Mouse 32k oligonucleotide (70mer) array. In VAD liver there was a decrease in expression of genes encoding enzymes of mitochondrial fatty acid (FA) oxidation; these genes included fatty acyl CoA ligase, carnitine o-palmitoyl transferase 1, medium chain acyl-CoA dehydrogenase, 3-ketoacyl CoA thiolase, and citrate synthase. Particularly affected was peroxisome metabolism, as genes encoding enzymes of peroxisomal FA oxidation and transport proteins were differentially expressed. These genes included those encoding acyl-CoA oxidase 1, the peroxisomal bifunctional enzyme, peroxisomal thiolase, and carnitine o-octanoyl transferase, the enzyme involved in shuttling FAs from the peroxisome to the mitochondrion. Most genes that were differentially expressed with chronic vitamin A depletion were responsive to treatment with all-trans retinoic acid (RA). Consistent with the decreased expression of genes involved in FA oxidation, we found an increase in hepatic macrocytic lipid accumulation and triglyceride levels. The relevant nuclear receptor gene that was differentially expressed in the VAD liver was that encoding the peroxisome proliferator-activated receptor (PPAR) alpha, the mRNA levels for which were decreased in VAD liver and increased with all-trans RA treatment. Down regulation of the PPAR alpha gene is the likely cause of the altered expression pattern of the above metabolic genes in VAD liver.
Mol Cell Endocrinol 2007 Jun 15
PMID:Altered lipid catabolism in the vitamin A deficient liver. 1746 65

High-oil maize as a product of long-term selection provides a unique resource for functional genomics. In this study, the abundant soluble proteins of early developing germs from high-oil and normal lines of maize were compared using two-dimensional gel electrophoresis (2-DGE) in combination with mass spectrometry (MS). More than 1100 protein spots were detected on electrophoresis maps of both high-oil and normal lines by using silver staining method. A total of 83 protein spots showed significant differential expression (>two-fold change; t-test: P < 0.05) between high-oil and normal inbred lines. Twenty-seven protein spots including 25 non-redundant proteins were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). Functional categorization of these proteins was carbohydrate metabolism, cytoskeleton, protein metabolism, stress response, and lipid metabolism. Three such proteins involved in lipid metabolism, namely putative enoyl-ACP reductase (ENR), putative stearoyl-ACP desaturase (SAD) and putative acetyl-CoA C-acyltransferase (ACA), had more abundant expressions in high-oil lines than in normal. At the mRNA expression level, SAD, ENR and ACA were expressed at significantly higher levels in high-oil lines than in normal. The results demonstrated that high expressions of SAD, ENR and ACA might be associated to increasing oil concentration in high-oil maize. This study represents the first proteomic analysis of high-oil maize and contributes to a better understanding of the molecular basis of oil accumulation in high-oil maize.
Mol Biol Rep 2009 Apr
PMID:Proteomic analysis of early germs with high-oil and normal inbred lines in maize. 1852 66

Kynurenine aminotransferase III (KAT III) has been considered to be involved in the production of mammalian brain kynurenic acid (KYNA), which plays an important role in protecting neurons from overstimulation by excitatory neurotransmitters. The enzyme was identified based on its high sequence identity with mammalian KAT I, but its activity toward kynurenine and its structural characteristics have not been established. In this study, the biochemical and structural properties of mouse KAT III (mKAT III) were determined. Specifically, mKAT III cDNA was amplified from a mouse brain cDNA library, and its recombinant protein was expressed in an insect cell protein expression system. We established that mKAT III is able to efficiently catalyze the transamination of kynurenine to KYNA and has optimum activity at relatively basic conditions of around pH 9.0 and at relatively high temperatures of 50 to 60 degrees C. In addition, mKAT III is active toward a number of other amino acids. Its activity toward kynurenine is significantly decreased in the presence of methionine, histidine, glutamine, leucine, cysteine, and 3-hydroxykynurenine. Through macromolecular crystallography, we determined the mKAT III crystal structure and its structures in complex with kynurenine and glutamine. Structural analysis revealed the overall architecture of mKAT III and its cofactor binding site and active center residues. This is the first report concerning the biochemical characteristics and crystal structures of KAT III enzymes and provides a basis toward understanding the overall physiological role of mammalian KAT III in vivo and insight into regulating the levels of endogenous KYNA through modulation of the enzyme in the mouse brain.
Mol Cell Biol 2009 Feb
PMID:Biochemical and structural properties of mouse kynurenine aminotransferase III. 2971 68

Infrared spectroscopy studies of beta-alkoxyvinyl trifluoromethyl ketone, with structure C(2)H(5)O-C(C(CH(3))(3))CH-COCF(3) (1), in twenty three different pure organic solvents were undertaken to investigate the solvent-solute interactions and to correlate solvent properties such as Reichard's parameter and solvatochromic parameters of Kamlet, Abbot, and Taft with carbonyl and vinyl stretching vibrations and their integrated intensities of existing spatial forms. It was shown that conjugation in CC-CO system of the (E-s-Z-o-Z) stereoisomer is higher than that in this system of the (Z-s-Z-o-Z) stereoisomer. From derived correlations of the v (CO) and v (CC) wavenumbers with solvatochromic parameters of Kamlet, Abbot, and Taft it is followed that the solvent polarity influences on the v (CO) and v (CC) wavenumbers more intense than the solvent HBD acidity, and, at the same time, the influence of these solvent properties is greater for the (E-s-Z-o-Z) stereoisomer. Analysis of derived KAT multiple regressions showed that the increase of the solvent polarity/polarizability (pi*) increased the conjugation in both stereoisomers, whereas the increase of the solvent HBD acidity (alpha) had opposite effect on conjugation in the (Z-s-Z-o-Z) and (E-s-Z-o-Z) stereoisomer. In the former case conjugation was weakened, whereas in the latter it was enhanced. These discrepancies were the consequence of different structure of H-bonded complexes between enone 1 and HBD solvents. The influence of the solvent HBA basicity (beta) also had peculiarity. The increase of the solvent HBA basicity disturbs the CC-CO conjugation in the (Z-s-Z-o-Z) stereoisomer due to carbonyl rotation, whereas in the (E-s-Z-o-Z) stereoisomer such increase enhanced this conjugation and, hence, increased the v (CO) and v (C==C) coupling.
Spectrochim Acta A Mol Biomol Spectrosc 2009 Mar
PMID:Solvent influence on the infrared spectra of beta-alkoxyvinyl methyl ketones II. Stretching vibrations and integrated intensities of carbonyl and vinyl bands of (3Z,E)-4-ethoxy-1,1,1-trifluoro-5,5-dimethylhex-3-en-2-one. 1911 4

As part of a study on aminotransferases, genes coding for putative enzymes from Trypanosoma brucei and Leishmania major (alanine aminotransferases: ALATs, Tb927.1.3950 and LmjF12.0630; kynurenine aminotransferase: KAT, Tb10.389.1810; and tyrosine aminotransferase: TAT, LmjF36.2360) were cloned and functionally expressed in Escherichia coli. The putative T. brucei KAT, in fact coded for a glutamine aminotransferase (GlnAT), which exhibited a notably high affinity (in the micromolar range) towards glutamine and cysteine; in addition, like bacterial GlnATs and mammalian KATs, it was able to utilize different 2-oxoacids as amino acceptors. L. major TAT resembled T. cruzi TAT in substrate specificity, although the leishmanial enzyme did not exhibit ALAT activity. On the other hand, T. brucei ALAT, shortened by the first 65 amino acids assigned in the data bases, was functional and actively transaminated the substrate pair l-alanine and 2-oxoglutarate. Moreover in Western blots, the molecular size of the protein detected in crude extracts of T. brucei procyclics was identical to the value of the recombinant enzyme. Like T. brucei and T. cruzi orthologues, L. major ALAT displayed narrow substrate specificity. The leishmanial ALAT, like the T. cruzi enzyme, exhibited a dual subcellular localization, in the cytosol and in the mitochondrion. In line with the findings of comparative proteomic analyses of insect and mammalian stages of T. brucei and Leishmania parasites, our results also showed that T. cruzi ALAT is constitutively expressed, with remarkably higher levels being detected in amastigotes than in epimastigotes. ALATs are expressed in the clinically important stages of TriTryps, probably fulfilling an essential role, which deserves further studies.
Mol Biochem Parasitol 2009 Aug
PMID:Functional characterization of stage-specific aminotransferases from trypanosomatids. 1944 56

NuA4, the major H4 lysine acetyltransferase (KAT) complex in Saccharomyces cerevisiae, is recruited to promoters and stimulates transcription initiation. NuA4 subunits contain domains that bind methylated histones, suggesting that histone methylation should target NuA4 to coding sequences during transcription elongation. We show that NuA4 is cotranscriptionally recruited, dependent on its physical association with elongating polymerase II (Pol II) phosphorylated on the C-terminal domain by cyclin-dependent kinase 7/Kin28, but independently of subunits (Eaf1 and Tra1) required for NuA4 recruitment to promoters. Whereas histone methylation by Set1 and Set2 is dispensable for NuA4's interaction with Pol II and targeting to some coding regions, it stimulates NuA4-histone interaction and H4 acetylation in vivo. The NuA4 KAT, Esa1, mediates increased H4 acetylation and enhanced RSC occupancy and histone eviction in coding sequences and stimulates the rate of transcription elongation. Esa1 cooperates with the H3 KAT in SAGA, Gcn5, to enhance these functions. Our findings delineate a pathway for acetylation-mediated nucleosome remodeling and eviction in coding sequences that stimulates transcription elongation by Pol II in vivo.
Mol Cell Biol 2009 Dec
PMID:NuA4 lysine acetyltransferase Esa1 is targeted to coding regions and stimulates transcription elongation with Gcn5. 1982 62

In the present study, we identified a missense mutation (G199V) in KAT-18 cell line established from primary cultures of anaplastic thyroid cancer (ATC). Notably, knockdown of this mutant (mt) p53 reduced cell viability and exerted antitumor activity equivalent to high doses of several chemotherapeutic agents. We showed that p53 knockdown had an antitumor effect via the induction of apoptosis. We further examined the underlying mechanism by which mt p53 (G199V) gains antiapoptotic function in KAT-18 cells. Microarray analysis revealed that p53 knockdown modified the expression of numerous apoptosis-related genes. Importantly, p53 knockdown led to downregulation of signal transducer and activator of transcription-3 (STAT3) gene expression. We further observed that p53 knockdown induced the downregulation of STAT3 protein. We also observed that a STAT3 inhibitor augmented the reduction of cell viability induced by p53 knockdown, whereas interleukin-6 treatment alleviated this effect. In addition, overexpression of STAT3 protected ATC cells against cell death induced by p53 knockdown. Taken together, these data show that mt p53 (G199V) gains antiapoptotic function mediated by STAT3 in ATC cells. Inhibition of the function of mt p53 (G199V) could be a novel and useful therapeutic strategy for decreasing the extent and severity of toxicity due to chemotherapeutic agents.
Mol Cancer Res 2009 Oct
PMID:Mutant p53 (G199V) gains antiapoptotic function through signal transducer and activator of transcription 3 in anaplastic thyroid cancer cells. 1982 93

Two types of thiolases are involved in the synthesis and catabolism of fatty acids; acetyl-CoA acetyltransferase (AT) which catalyzes the formation of acetoacetyl-CoA from acetyl-CoA by transferring an acetyl group from one acetyl-CoA molecule to another, and 3-ketoacyl-CoA thiolase which catalyzes a reversible thiolytic cleavage of 3-ketoacyl-CoA into acetyl-CoA and acyl-CoA. Although many mammalian thiolases have been characterized in detail, no thiolases from insects have been functionally characterized to date. Here we report first characterization of an insect AT gene, Osat1, from the pheromone gland of the adzuki bean borer moth Ostrinia scapulalis (Lepidoptera; Crambidae). Osat1 encodes a 41.2 kDa protein comprising 396 amino acid residues (OsAT1), which possesses structural features of the thiolase family. An Osat1 homologue of Bombyx mori (Bmat1) was cloned through exploration of an EST library of the silkworm. Subsequent survey of the genome database revealed that B. mori has at least six Osat1 homologues, among which Bmat1 was most closely related to Osat1. We expressed recombinant OsAT1 using a baculovirus expression system, and verified that OsAT1 catalyzes the formation of acetoacetyl-CoA from acetyl-CoA. Osat1 was expressed in all adult tissues examined. These results indicate that OsAT1 is a functional AT ubiquitously expressed in O. scapulalis tissues.
Insect Biochem Mol Biol 2010 Jan
PMID:Molecular and functional characterization of an acetyl-CoA acetyltransferase from the adzuki bean borer moth Ostrinia scapulalis (Lepidoptera: Crambidae). 2004 99


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