Vitamin B6 conjugation to nuclear corepressor RIP140 and its role in gene regulation

Department of Pharmacology, Molecular Biology and Biophysics, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, Minnesota 55455, USA.
Nature Chemical Biology (Impact Factor: 13). 04/2007; 3(3):161-5. DOI: 10.1038/nchembio861
Source: PubMed


Pyridoxal 5'-phosphate (PLP), the biologically active form of vitamin B6, is an important cofactor in amino acid metabolism, and supplementary vitamin B6 has protective effects in many disorders. Other than serving as a cofactor, it can also modulate the activities of steroid hormone receptors and transcription factors. However, the molecular basis of this modulation is unclear. Here, we report that mouse nuclear receptor interacting protein 140 (RIP140) can be modified by PLP conjugation. We mapped the modification site to Lys613 by LC-ESI-MS/MS analysis. This modification enhanced its transcriptional corepressive activity and its physiological function in adipocyte differentiation. We attribute this effect to increased interaction of RIP140 with histone deacetylases and nuclear retention of RIP140. This study uncovers a new physiological role of vitamin B6 in gene regulation by PLP conjugation to a transcriptional coregulator, which represents a new function of an old form of protein post-translational modification that has important biological consequences.

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    • "Most of these enzymes are involved in amino acid metabolism. It has also been shown that the DNA-binding activity of transcription factors is modulated by PLP (Belitsky, 2004a; Belitsky, 2014; Edayathumangalam et al., 2013; El Qaidi et al., 2013; Huq et al., 2007; Oka et al., 2001). The second essential B6 vitamer PMP serves as a cofactor in the biosynthesis of deoxysugars, which play a role as bacterial surface antigens (Romo and Liu, 2011). "
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    ABSTRACT: Vitamin B6 is a designation for the vitamers pyridoxine, pyridoxal, pyridoxamine, and their respective 5'-phosphates. Pyridoxal 5'-phosphate, the biologically most-important vitamer, serves as a cofactor for many enzymes, mainly active in amino acid metabolism. While microorganisms and plants are capable of synthesizing vitamin B6, other organisms have to ingest it. The vitamer pyridoxine, which is used as a dietary supplement for animals and humans is commercially produced by chemical processes. The development of potentially more cost-effective and more sustainable fermentation processes for pyridoxine production is of interest for the biotech industry. We describe the generation and characterization of a Bacillus subtilis pyridoxine production strain overexpressing five genes of a non-native deoxyxylulose 5'-phosphate-dependent vitamin B6 pathway. The genes, derived from Escherichia coli and Sinorhizobium meliloti, were assembled to two expression cassettes and introduced into the B. subtilis chromosome. In vivo complementation assays revealed that the enzymes of this pathway were functionally expressed and active. The resulting strain produced 14mg/l pyridoxine in a small-scale production assay. By optimizing the growth conditions and co-feeding of 4-hydroxy-threonine and deoxyxylulose the productivity was increased to 54mg/l. Although relative protein quantification revealed bottlenecks in the heterologous pathway that remain to be eliminated, the final strain provides a promising basis to further enhance the production of pyridoxine using B. subtilis.
    Metabolic Engineering 06/2014; 25. DOI:10.1016/j.ymben.2014.06.007 · 6.77 Impact Factor
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    • "According to functional enrichment analysis using KEGG pathway terms, vitamin B6 metabolism (bta00750, p-value = 0.025) was significantly enriched, including the aldehyde oxidase 1 (AOX1) gene in Hanwoo (Additional file 10). Vitamin B6 induces the differentiation of adipocytes from pre-adipocytes and facilitates fat accumulation [29]. In particular, the AOX1 gene is a target of peroxisome proliferator-activated receptors alpha and gamma (PPARα and PPARγ) as a key gene in adipogenesis [30]. "
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    ABSTRACT: Hanwoo (Korean cattle), which originated from natural crossbreeding between taurine and zebu cattle, migrated to the Korean peninsula through North China. Hanwoo were raised as draft animals until the 1970s without the introduction of foreign germplasm. Since 1979, Hanwoo has been bred as beef cattle. Genetic variation was analyzed by whole-genome deep resequencing of a Hanwoo bull. The Hanwoo genome was compared to that of two other breeds, Black Angus and Holstein, and genes within regions of homozygosity were investigated to elucidate the genetic and genomic characteristics of Hanwoo. The Hanwoo bull genome was sequenced to 45.6-fold coverage using the ABI SOLiD system. In total, 4.7 million single-nucleotide polymorphisms and 0.4 million small indels were identified by comparison with the Btau4.0 reference assembly. Of the total number of SNPs and indels, 58% and 87%, respectively, were novel. The overall genotype concordance between the SNPs and BovineSNP50 BeadChip data was 96.4%. Of 1.6 million genetic differences in Hanwoo, approximately 25,000 non-synonymous SNPs, splice-site variants, and coding indels (NS/SS/Is) were detected in 8,360 genes. Among 1,045 genes containing reliable specific NS/SS/Is in Hanwoo, 109 genes contained more than one novel damaging NS/SS/I. Of the genes containing NS/SS/Is, 610 genes were assigned as trait-associated genes. Moreover, 16, 78, and 51 regions of homozygosity (ROHs) were detected in Hanwoo, Black Angus, and Holstein, respectively. 'Regulation of actin filament length' was revealed as a significant gene ontology term and 25 trait-associated genes for meat quality and disease resistance were found in 753 genes that resided in the ROHs of Hanwoo. In Hanwoo, 43 genes were located in common ROHs between whole-genome resequencing and SNP chips in BTA2, 10, and 13 coincided with quantitative trait loci for meat fat traits. In addition, the common ROHs in BTA2 and 16 were in agreement between Hanwoo and Black Angus. We identified 4.7 million SNPs and 0.4 million small indels by whole-genome resequencing of a Hanwoo bull. Approximately 25,000 non-synonymous SNPs, splice-site variants, and coding indels (NS/SS/Is) were detected in 8,360 genes. Additionally, we found 25 trait-associated genes for meat quality and disease resistance among 753 genes that resided in the ROHs of Hanwoo. These findings will provide useful genomic information for identifying genes or casual mutations associated with economically important traits in cattle.
    BMC Genomics 07/2013; 14(1):519. DOI:10.1186/1471-2164-14-519 · 3.99 Impact Factor
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    • "However, a reduced V max and unaltered K m would also be consistent with a decrease in active enzyme which is also suggested by the observed reduction of AADC protein and expression, consequently inhibition alone is unlikely to account for the loss in AADC activity. PLP has previously been demonstrated to interact with transcription factors (Allgood et al. 1993; Huq et al. 2007), it could be that 4-deoxypyri- doxine or its phosphorylated form inhibits an interaction of PLP with a transcription factor and that this interaction led to the observed decrease in AADC expression. That a PLP antagonist can reduce AADC expression is a possible indication that PLP may be involved in the control of AADC expression. "
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    ABSTRACT: J. Neurochem. (2010) 114, 87–96. Pyridoxal 5′-phosphate, the active form of vitamin B6, is an essential cofactor for multiple enzymes, including aromatic l-amino acid decarboxylase that catalyses the final stage in the production of the neurotransmitters dopamine and serotonin. In two patients with inherited disorders of vitamin B6 metabolism, we observed reductions in plasma aromatic l-amino acid decarboxylase activity. In one patient, this change was related to an increase in Km for pyridoxal 5′-phosphate. Furthermore, pyridoxal 5′-phosphate-deficient human SH-SY5Y neuroblastoma cells were found to exhibit reduced levels of aromatic l-amino acid decarboxylase activity and protein but with no alteration in expression. Further reductions in activity and protein were observed with the addition of the vitamin B6 antagonist 4-deoxypyridoxine, which also reduced aromatic l-amino acid decarboxylase mRNA levels. Neither pyridoxal 5′-phosphate deficiency nor the addition of 4-deoxypyridoxine affected aromatic l-amino acid decarboxylase stability over 8 h with protein synthesis inhibited. Increasing extracellular availability of pyridoxal 5′-phosphate was not found to have any significant effect on intracellular pyridoxal 5′-phosphate concentrations or on aromatic l-amino acid decarboxylase. These findings suggest that maintaining adequate pyridoxal 5′-phosphate availability may be important for optimal treatment of aromatic l-amino acid decarboxylase deficiency and l-dopa-responsive conditions.
    Journal of Neurochemistry 07/2010; 114(1):87-96. DOI:10.1111/j.1471-4159.2010.06742.x · 4.28 Impact Factor
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