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1
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Metabolic enzymes that bind RNA: yet another level of cellular regulatory network?

100%
Cieśla J.
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2006
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vol. 53
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issue 1
11-32
EN
Several enzymes that were originally characterized to have one defined function in intermediatory metabolism are now shown to participate in a number of other cellular processes. Multifunctional proteins may be crucial for building of the highly complex networks that maintain the function and structure in the eukaryotic cell possessing a relatively low number of protein-encoding genes. One facet of this phenomenon, on which I will focus in this review, is the interaction of metabolic enzymes with RNA. The list of such enzymes known to be associated with RNA is constantly expanding, but the most intriguing question remains unanswered: are the metabolic enzyme-RNA interactions relevant in the regulation of cell metabolism? It has been proposed that metabolic RNA-binding enzymes participate in general regulatory circuits linking a metabolic function to a regulatory mechanism, similar to the situation of the metabolic enzyme aconitase, which also functions as iron-responsive RNA-binding regulatory element. However, some authors have cautioned that some of such enzymes may merely represent "molecular fossils" of the transition from an RNA to a protein world and that the RNA-binding properties may not have a functional significance. Here I will describe enzymes that have been shown to interact with RNA (in several cases a newly discovered RNA-binding protein has been identified as a well-known metabolic enzyme) and particularly point out those whose ability to interact with RNA seems to have a proven physiological significance. I will also try to depict the molecular switch between an enzyme's metabolic and regulatory functions in cases where such a mechanism has been elucidated. For most of these enzymes relations between their enzymatic functions and RNA metabolism are unclear or seem not to exist. All these enzymes are ancient, as judged by their wide distribution, and participate in fundamental biochemical pathways.
2
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Phosphorylation of basic amino acid residues in proteins: important but easily missed

51%
Cieśla J., Frączyk T., Rode W.
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2011
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vol. 58
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issue 2
137-148
EN
Reversible phosphorylation is the most widespread posttranslational protein modification, playing regulatory role in almost every aspect of cell life. The majority of protein phosphorylation research has been focused on serine, threonine and tyrosine that form acid-stable phosphomonoesters. However, protein histidine, arginine and lysine residues also may undergo phosphorylation to yield acid-labile phosphoramidates, most often remaining undetected in conventional studies of protein phosphorylation. It has become increasingly evident that acid-labile protein phosphorylations play important roles in signal transduction and other regulatory processes. Beside acting as high-energy intermediates in the transfer of the phosphoryl group from donor to acceptor molecules, phosphohistidines have been found so far in histone H4, heterotrimeric G proteins, ion channel KCa3.1, annexin 1, P-selectin and myelin basic protein, as well as in recombinant thymidylate synthase expressed in bacterial cells. Phosphoarginines occur in histone H3, myelin basic protein and capsidic protein VP12 of granulosis virus, whereas phospholysine in histone H1. This overview of the current knowledge on phosphorylation of protein basic amino-acid residues takes into consideration its proved or possible roles in cell functioning. Specific requirements of studies on acid-labile protein phosphorylation are also indicated.
3
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Altered mouse leukemia L1210 thymidylate synthase, associated with cell resistance to 5-fluoro-dUrd, is not mutated but rather reflects posttranslational modification

45%
Cieśla J., Frączyk T., Zieliński Z., Sikora J., Rode W.
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2006
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vol. 53
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issue 1
189-198
EN
Thymidylate synthase purified from 5-fluoro-dUrd-resistant mouse leukemia L1210 cells (TSr) was less sensitive to slow-binding inhibition by 5-fluoro-dUMP than the enzyme from the parental cells (TSp), both enzyme forms differing also in sensitivity to several other dump analogues, apparent molecular weights of monomer and dimer, and temperature dependence of the catalyzed reaction. Direct sequencing of products obtained from RT-PCR, performed on total RNA isolated from the parental and 5-fluoro-dUrd-resistant cells, proved both nucleotide sequences to be identical to the mouse thymidylate synthase coding sequence published earlier (NCBI protein database access no. NP_067263). This suggests that the altered properties of TSr are caused by a factor different than protein mutation, presumably posttranslational modification. As a possibility of rat thymidylate synthase phosphorylation has been recently demonstrated (Samsonoff et al. (1997) J Biol Chem 272: 13281), the mouse enzyme amino-acid sequence was analysed, revealing several potential phosphorylation sites. In order to test possible influence of the protein phosphorylation state on enzymatic properties, endogenous TSp and TSr were purified in the presence of inhibitors of phosphatases. Although both enzyme forms were phosphorylated, as shown by electrophoretical separation followed by phosphoprotein detection, the extent of phosphorylation was apparently similar. However, the same two purified enzyme preparations, compared to the corresponding preparations purified in the absence of phosphatase inhibitors, showed certain properties, including sensitivity to the slow-binding inhibition by FdUMP, altered. Thus properties dependence on phosphorylation was indicated.
4
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Thymidylate synthase in the development of Hymenolepis diminutu

45%
Cieśla J., Zieliński Z., Machnicka B., Rode W.
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issue 3
291-298
5
Content available remote

The effect of Arg209 to Lys mutation in mouse thymidylate synthase.

39%
Cieśla J., Gołos B., Wałajtys-Rode E., Jagielska E., Płucienniczak A., Rode W.
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2002
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vol. 49
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issue 3
651-658
EN
Mouse thymidylate synthase R209K (a mutation corresponding to R218K in Lactobacillus casei), overexpressed in thymidylate synthase-deficient Escherichia coli strain, was poorly soluble and with only feeble enzyme activity. The mutated protein, incubated with FdUMP and N5,10-methylenetetrahydrofolate, did not form a complex stable under conditions of SDS/polyacrylamide gel electrophoresis. The reaction catalyzed by the R209K enzyme (studied in a crude extract), compared to that catalyzed by purified wild-type recombinant mouse thymidylate synthase, showed the Km value for dUMP 571-fold higher and Vmax value over 50-fold (assuming that the mutated enzyme constituted 20% of total crude extract protein) lower. Thus the ratios kcat, R209K/kcat, 'wild' and (kcat, R209K/Km, R209KdUMP)/( kcat, 'wild'/Km, 'wild'dUMP) were 0.019 and 0.000032, respectively, documenting that mouse thymidylate synthase R209, similar to the corresponding L. casei R218, is essential for both dUMP binding and enzyme reaction.
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