Urotensin-II was originally isolated from the goby urophysis in the 1960s as a vasoactive peptide with a prominent role in cardiovascular homeostasis. The identification of human isoform of urotensin-II and its specific UT receptor by Ames et al. in 1999 led to investigating the putative role of the interaction U-II/UT receptor in multiple pathophysiological effects in humans. Since urotensin-II is widely expressed in several peripheral tissues including cardiovascular system, the design and development of novel urotensin-II analogues can improve knowledge about structure-activity relationships (SAR). In particular, since the modulation of the U-II system offers a great potential for therapeutic strategies related to the treatment of several diseases, like cardiovascular diseases, the research of selective and potent ligands at UT receptor is more fascinating. In this paper, we review the developments of peptide and nonpeptide U-II structures so far developed in order to contribute also to a more rational and detectable design and synthesis of new molecules with high affinity at the UT receptor.

Francesco Merlino

Salvatore Di Maro

Ali Munaim Yousif

Michele Caraglia

Paolo Grieco

Urotensin-II Ligands: An Overview from Peptide to Nonpeptide Structures

A new cysteine protease named Nivulian-II has been purified from the latex of Euphorbia nivulia Buch.-Ham. The apparent molecular mass of Nivulian-II is 43670.846 Da (MALDI TOF/MS). Peptide mass fingerprint analysis revealed peptide matches to Maturase K (Q52ZV1&#x5f;9MAGN) of Banksia quercifolia. The N-terminal sequence (DFPPNTCCCICC) showed partial homology with those of other cysteine proteinases of biological origin. This is the first paper to characterize a Nivulian-II of E. nivulia latex with respect to amino acid sequencing.

Shamkant B. Badgujar

Raghunath T. Mahajan

Peptide Mass Fingerprinting and N-Terminal Amino Acid Sequencing of Glycosylated Cysteine Protease of Euphorbia nivulia Buch.-Ham.

Catabolite repression (CCR) regulates amino acid permeases in Saccharomyces cerevisiae via a TOR-kinase mediated mechanism. When glucose, the preferred fuel in S. cerevisiae, is substituted by galactose, amino acid uptake is increased. Here we have assessed the contribution and metabolic significance of this surfeit of amino acid in yeast undergoing catabolite derepression (CDR). L-[U-14C]leucine oxidation was increased 15 &#xb1; 1 fold in wild type (WT) strain grown in galactose compared to glucose. Under CDR, leucine oxidation was (i) proportional to uptake, as demonstrated by decreased uptake and oxidation of leucine in strains deleted of major leucine permeases and (ii) entirely dependent upon the TCA cycle, as cytochrome c1 (Cyt1) deleted strains could not grow in galactose. A regulator of amino acid carbon entry into the TCA cycle, branched chain ketoacid dehydrogenase, was also increased 29 &#xb1; 3 fold under CCR in WT strain. Protein expression of key TCA cycle enzymes, citrate synthase (Cs), and Cyt1 was increased during CDR. In summary, CDR upregulation of amino acid uptake is accompanied by increased utilization of amino acids for yeast growth. The mechanism for this is likely to be an increase in protein expression of key regulators of the TCA cycle.

John S. Hothersall

Aamir Ahmed

Metabolic Fate of the Increased Yeast Amino Acid Uptake Subsequent to Catabolite Derepression

The transformation of the strain <svg style="vertical-align:-0.1638pt;width:61.787498px;" id="M1" height="16.525" version="1.1" viewBox="0 0 61.787498 16.525" width="61.787498" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> with plasmid vector pET11a containing the cloned gene of bacterial selenophosphate synthetase (SPS), selD, from the E. coli BL21-Gold (DE3) strain gives an overproducing strain of SPS with one synonymic substitution, E197D. The transformation efficiency was estimated as 8 &#xd7; 108 CFU/&#x3bc;g plasmid DNA. 28&#x2009;mg of highly purified preparation of recombinant SPS capable of binding TNP-ATP was eluted from DEAE-Sephadex column in amount of 15 &#x25; from the total soluble protein in crude extract. The fluorescent derivative of ATP, 2&#x2032;(3&#x2032;)-O-(2,4,6-trinitrophenyl)adenosine-5&#x2032;-triphosphate (TNP-ATP), was used as a synthetic analog of the substrate for the monitoring and quantitative analysis of the functional activity of SPS. The non-linear regression analysis of the saturation curve of TNP-ATP binding to D197 SPS with GraphPad Prism software fits to a model with 2 distinct binding sites with <svg style="vertical-align:-3.27605pt;width:27.174999px;" id="M3" height="15.25" version="1.1" viewBox="0 0 27.174999 15.25" width="27.174999" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>
 different in order. The SPS existence in a form of tetramer in given reaction conditions, in accordance with the concentration stoichiometry of 4 moles of TNP-ATP to 1 mole of recombinant protein, is being discussed. The tetramer structure was predicted with molecular modelling software YASARA and modelled in vacuum using steepest descent minimization energy method. We hypothesize here the recombinant SPS exists as a dimer in solution with two active sites capable of ATP binding in each subunit.

Y. V. Preobrazhenskaya

A. I. Stenko

M. V. Shvarts

V. Y. Lugovtsev

Binding Stoichiometry of a Recombinant Selenophosphate Synthetase with One Synonymic Substitution E197D to a Fluorescent Nucleotide Analog of ATP, TNP-ATP

We have demonstrated that the peptide L-2 designed from an alanine scanning of the Limulus-derived LALF32-51 region is a potential candidate for the anticancer therapy and its cell-penetrating capacity is an associated useful property. By the modification in the primary structure of L-2, a second-generation peptide (CIGB-552) was developed. However, the molecular mechanism underlying its cytotoxic activity remains partially unknown. In this study, it was shown that CIGB-552 increases the levels of COMMD1, a protein involved in copper homeostasis, sodium transport, and the NF-&#x3ba;B signaling pathway. We found that CIGB-552 induces ubiquitination of RelA and inhibits the antiapoptotic activity regulated by NF-&#x3ba;B, whereas the knockdown of COMMD1 blocks this effect. We also found that CIGB-552 decreases the antioxidant capacity and induces the peroxidation of proteins and lipids in the tumor cells. Altogether, this study provides new insights into the mechanism of action of the peptide CIGB-552, which could be relevant in the design of future anticancer therapies.

Julio R. Fern&#xe1;ndez Mass&#xf3;

Brizaida Oliva Arg&#xfc;elles

Yelaine Tejeda

Soledad Astrada

Hilda Garay

Osvaldo Reyes

Livan Delgado-Roche

Mariela Bollati-Fogol&#xed;n

Maribel G. Vallesp&#xed;

The Antitumor Peptide CIGB-552 Increases COMMD1 and Inhibits Growth of Human Lung Cancer Cells

Ischemia enhanced release of endogenous neuroactive amino acids from cerebellar and cerebral cortical slices. More glutamate was released in adult than developing mice. Taurine release enhanced by K+ stimulation and ischemia was more than one magnitude greater than that of GABA or glutamate in the developing cerebral cortex and cerebellum, while in adults the releases were almost comparable. Aspartate release was prominently enhanced by both ischemia and K+ stimulation in the adult cerebral cortex. In the cerebellum K+ stimulation and ischemia evoked almost 10-fold greater GABA release in 3-month olds than in 7-day olds. The release of taurine increased severalfold in the cerebellum of 7-day-old mice in high-K+ media, whereas the K+-evoked effect was rather small in adults. In 3-month-old mice no effects of K+ stimulation or ischemia were seen in the release of aspartate, glycine, glutamine, alanine, serine, or threonine. The releases from the cerebral cortex and cerebellum were markedly different and also differed between developing and adult mice. In developing mice only the release of inhibitory taurine may be large enough to counteract the harmful effects of excitatory amino acids in ischemia in both cerebral cortex and cerebellum, in particular since at that age the release of glutamate and aspartate cannot be described as massive.

Simo S. Oja

Pirjo Saransaari

Ischemia Induces Release of Endogenous Amino Acids from the Cerebral Cortex and Cerebellum of Developing and Adult Mice

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Journal of Amino Acids