Peptidomimetics – An infinite reservoir of metal binding motifs in metabolically stable and biologically active molecules

2021 ◽  
Vol 217 ◽  
pp. 111386
Author(s):  
Joanna Wątły ◽  
Adriana Miller ◽  
Henryk Kozłowski ◽  
Magdalena Rowińska-Żyrek
Keyword(s):  
Metal Binding ◽  
Biologically Active ◽  
Binding Motifs ◽  
Infinite Reservoir

scholarly journals Contributions of Zur-Controlled Ribosomal Proteins to Growth under Zinc Starvation Conditions

2009 ◽  
Vol 191 (19) ◽  
pp. 6116-6122 ◽  
Author(s):  
Scott E. Gabriel ◽  
John D. Helmann
Keyword(s):  
Metal Binding ◽  
Ribosomal Proteins ◽  
Growth Defect ◽  
Poor Growth ◽  
Intracellular Zinc ◽  
Binding Motifs ◽  
Relevant Role ◽  
Biochemical Analyses ◽  
Zinc Levels ◽  
Starvation Conditions

ABSTRACT Maintaining intracellular zinc levels is critical, because zinc serves as a cofactor for many required enzymes and is toxic in excess. Bacillus subtilis Zur, a Fur family repressor, controls the zinc starvation response including two ribosomal proteins (r-proteins) paralogous to L31 and S14. Biochemical analyses suggest that Zur-controlled r-proteins (which lack the two CXXC metal-binding motifs) may functionally replace their cognate zinc-requiring proteins during zinc limitation. We demonstrate here that Zur regulates the expression of an additional r-protein paralog, RpmGC (L33c), and, using strains defective in zinc uptake, we investigate the physiological contributions of all three Zur-regulated r-proteins. In the 168 lineage, rpmGC is a pseudogene containing a frameshift mutation. Correction of this mutation allows expression of a functional L33c that can suppress the poor growth phenotype of an rpmGA rpmGB (encoding L33a, L33b) double mutant. Similarly, we provide physiological evidence in support of the “failsafe” model (Y. Natori et al., Mol. Microbiol. 63:294-307, 2007) in which the Zur-regulated S14 paralog YhzA allows continued ribosome synthesis when there is insufficient zinc to support S14 function. The L31 paralog YtiA can replace L31 and complement the growth defect of an rpmE mutant (Nanamiya et al., Mol. Microbiol. 52:273-283). We show that, under zinc starvation conditions, derepression of YtiA significantly increases the growth of cells in which preexisting ribosomes carry, as the sole L31 protein, RpmE (containing zinc), but not if they carry YtiA (which lacks zinc). These results support a direct and physiologically relevant role for YtiA in mobilizing zinc from ribosomes.

Stability Constants of Some Metal Complexes Formed by Mimosine and Related Compounds

1979 ◽  
Vol 32 (1) ◽  
pp. 21 ◽  
Author(s):  
H Stunzi ◽  
DD Perrin ◽  
T Teitei ◽  
RLN Harris
Keyword(s):  
Amino Acid ◽  
Stability Constants ◽  
Metal Binding ◽  
Acid Group ◽  
Biologically Active ◽  
Amino Acid Group ◽  
Dimeric Complexes ◽  
Major Species ◽  
Active Amino Acid ◽  
Related Compounds

Complex formation of the biologically active amino acid L-mimosine [α-amino-β-(3-hydroxy-4-oxo-1,4-dihydropyridin-1-yl)propanoic acid (1)], mimosinic acid (2), mimosine methyl ether (9) and 3-hydroxy-1-methylpyridin-4(1H)-one (4) with Cu2+, Zn2+, Cd2+ and Pb2+ was studied. Stability constants were determined by potentiometric titration in 0.15M KNOB3 as inert electrolyte at 37�. In the monomeric complexes formed by the mimosine derivatives, metal binding by the hydroxypyridone moiety was favoured relative to the amino acid group. With mimosine, dimeric complexes were major species. Under physiological conditions, mimosine binds copper and zinc ions more strongly than do simpler amino acids.

Sequence Analysis of a Subset of Plasma Membrane Raft Proteome Containing CXXC Metal Binding Motifs

2015 ◽  
Vol 5 (2) ◽  
pp. 1-15
Author(s):  
Santosh Kumar Sahu ◽  
Himadri Gourav Behuria ◽  
Sangam Gupta ◽  
Babita Sahoo
Keyword(s):  
Plasma Membrane ◽  
Metal Binding ◽  
Mammalian Cells ◽  
Membrane Raft ◽  
Binding Motifs ◽  
Cxxc Motif ◽  
Signaling Mechanisms ◽  
Associated Proteins ◽  
Heavy Metal Sensing ◽  
Metal Sensing

In an attempt to identify the metal sensing proteins localized to mammalian plasma membrane, the authors screened a list of 300 raft associated proteins that are involved in cellular signaling mechanisms by searching the presence of metal thionin (CXXC) motifs. 50 proteins were found to possess CXXC motifs that could act as potential metal sensing proteins. The authors determined membrane topologies of the above CXXC motif containing proteins using TM-pred and analyzed the positions of their transmembrane (TM) domains using Bio-edit software. Based on the topology of CXXC domains, the authors classified all the raft-associated metal sensing proteins into six categories. They are (i) Exoplasmic tails with CXXC motif, (ii) Exoplasmic loops with CXXC motif, (iii) Cytosolic tails with CXXC motif, (iv) Cytosolic loop with CXXC motif, (v) TM domains with CXXC motifs, (vi) Proteins with multiple topologies of CXXC motif. The authors' study will lead to understanding of the raft-mediated mechanism of heavy metal sensing and signaling in mammalian cells.

scholarly journals Trinuclear metal clusters in catalysis by terpenoid synthases

2010 ◽  
Vol 82 (8) ◽  
pp. 1585-1597 ◽  
Author(s):  
Julie A. Aaron ◽  
David W. Christianson
Keyword(s):  
Metal Binding ◽  
Amino Acid Sequence Identity ◽  
Metal Clusters ◽  
Metal Cluster ◽  
Crystal Structure Analysis ◽  
Class I ◽  
Binding Motifs ◽  
Sequence Identity ◽  
Leaving Group ◽  
Terpenoid Synthase

Terpenoid synthases are ubiquitous enzymes that catalyze the formation of structurally and stereochemically diverse isoprenoid natural products. Many isoprenoid coupling enzymes and terpenoid cyclases from bacteria, fungi, protists, plants, and animals share the class I terpenoid synthase fold. Despite generally low amino acid sequence identity among these examples, class I terpenoid synthases contain conserved metal-binding motifs that coordinate to a trinuclear metal cluster. This cluster not only serves to bind and orient the flexible isoprenoid substrate in the precatalytic Michaelis complex, but it also triggers the departure of the diphosphate leaving group to generate a carbocation that initiates catalysis. Additional conserved hydrogen bond donors assist the metal cluster in this function. Crystal structure analysis reveals that the constellation of three metal ions required for terpenoid synthase catalysis is generally identical among all class I terpenoid synthases of known structure.

scholarly journals The UDP-diacylglucosamine Pyrophosphohydrolase LpxH in Lipid A Biosynthesis Utilizes Mn2+ Cluster for Catalysis

2013 ◽  
Vol 288 (38) ◽  
pp. 26987-27001 ◽  
Author(s):  
Hayley E. Young ◽  
Matthew P. Donohue ◽  
Tatyana I. Smirnova ◽  
Alex I. Smirnov ◽  
Pei Zhou
Keyword(s):  
Metal Binding ◽  
Lipid A ◽  
Structural Investigation ◽  
Enzymatic Assays ◽  
Binding Motifs ◽  
Conserved Residues ◽  
Fourth Step ◽  
Lipid A Biosynthesis ◽  
Fold Stimulation

In Escherichia coli and the majority of β- and γ-proteobacteria, the fourth step of lipid A biosynthesis, i.e. cleavage of the pyrophosphate group of UDP-2,3-diacyl-GlcN, is carried out by LpxH. LpxH has been previously suggested to contain signature motifs found in the calcineurin-like phosphoesterase (CLP) family of metalloenzymes; however, it cleaves a pyrophosphate bond instead of a phosphoester bond, and its substrate contains nucleoside diphosphate moieties more common to the Nudix family rather than to the CLP family. Furthermore, the extent of biochemical data fails to demonstrate a significant level of metal activation in enzymatic assays, which is inconsistent with the behavior of a metalloenzyme. Here, we report cloning, purification, and detailed enzymatic characterization of Haemophilus influenzae LpxH (HiLpxH). HiLpxH shows over 600-fold stimulation of hydrolase activity in the presence of Mn2+. EPR studies reveal the presence of a Mn2+ cluster in LpxH. Finally, point mutants of residues in the conserved metal-binding motifs of the CLP family greatly inhibit HiLpxH activity, highlighting their importance in enzyme function. Contrary to previous analyses of LpxH, we find HiLpxH does not obey surface dilution kinetics. Overall, our work unambiguously establishes LpxH as a calcineurin-like phosphoesterase containing a Mn2+ cluster coordinated by conserved residues. These results set the scene for further structural investigation of the enzyme and for design of novel antibiotics targeting lipid A biosynthesis.

scholarly journals In silico identification of putative metal binding motifs

2006 ◽  
Vol 23 (3) ◽  
pp. 267-271 ◽  
Author(s):  
R. Thilakaraj ◽  
K. Raghunathan ◽  
S. Anishetty ◽  
G. Pennathur
Keyword(s):  
Metal Binding ◽  
In Silico ◽  
Binding Motifs ◽  
In Silico Identification

scholarly journals Zn2+ and Cu2+ Binding to the Extramembrane Loop of Zrt2, a Zinc Transporter of Candida albicans

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 121
Author(s):  
Denise Bellotti ◽  
Adriana Miller ◽  
Magdalena Rowińska-Żyrek ◽  
Maurizio Remelli
Keyword(s):  
Candida Albicans ◽  
Binding Site ◽  
Metal Binding ◽  
Zinc Transporter ◽  
Serine Residue ◽  
Metal Binding Site ◽  
Binding Motifs ◽  
Zip Family ◽  
Acidic Conditions ◽  
Disordered Loop

Zrt2 is a zinc transporter of the ZIP family. It is predicted to be located in the plasma membrane and it is essential for Candida albicans zinc uptake and growth at acidic pH. Zrt2 from C. albicans is composed of 370 amino acids and contains eight putative transmembrane domains and an extra-membrane disordered loop, corresponding to the amino acid sequence 126–215. This protein region contains at least three possible metal binding motifs: HxHxHxxD (144–153), HxxHxxEHxD (181–193) and the Glu- and Asp- rich sequence DDEEEDxE (161–168). The corresponding model peptides, protected at their termini (Ac-GPHTHSHFGD-NH2, Ac-DDEEEDLE-NH2 and Ac-PSHFAHAQEHQDP-NH2), have been investigated in order to elucidate the thermodynamic and coordination properties of their Zn2+ and Cu2+ complexes, with the further aim to identify the most effective metal binding site among the three fragments. Furthermore, we extended the investigation to the peptides Ac-GPHTHAHFGD-NH2 and Ac-PAHFAHAQEHQDP-NH2, where serine residues have been substituted by alanines in order to check if the presence of a serine residue may favor the displacement of amidic protons by Cu2+. In the native Zrt2 protein, the Ac-GPHTHSHFGD-NH2 region of the Zrt2 loop has the highest metal binding affinity, showing that three alternated histidines separated by only one residue (-HxHxH-) bind Zn2+ and Cu2+ more strongly than the region in which three histidines are separated by two and three His residues (-HxxHxxxH- in Ac-PSHFAHAQEHQDP-NH2). All studied Zrt2 loop fragments have lower affinity towards Zn2+ than the zinc(II) binding site on the Zrt1 transporter; also, all three Zrt2 regions bind Zn2+ and Cu2+ with comparable affinity below pH 5 and, therefore, may equally contribute to the metal acquisition under the most acidic conditions in which the Zrt2 transporter is expressed.

The v-ski oncogene encodes a truncated set of c-ski coding exons with limited sequence and structural relatedness to v-myc

1989 ◽  
Vol 9 (9) ◽  
pp. 4038-4045
Author(s):  
E Stavnezer ◽  
D Brodeur ◽  
L A Brennan
Keyword(s):  
Amino Acid ◽  
Metal Binding ◽  
Avian Leukosis Virus ◽  
Amino Acid Sequences ◽  
Biologically Active ◽  
Predicted Amino Acid Sequence ◽  
Base Sequence ◽  
Reading Frame ◽  
Metal Binding Domain ◽  
Virus C

The nucleotide sequence of a biologically active v-ski gene from a cloned proviral segment shows that ski is a 1,312-base sequence embedded in the p19 region of the avian leukosis virus gag gene. The v-ski sequence contains a single open translational reading frame that encodes a polypeptide with a molecular mass of 49,000 daltons. The predicted amino acid sequence includes nuclear localization motifs that have been identified in other nuclear oncoproteins. It also contains a proline-rich region and a set of cysteine and histidine residues that could constitute a metal-binding domain. Two regions of the amino acid sequences of v-ski and v-myc are related, and the two proteins exhibit similar distributions of hydrophobic and hydrophilic amino acids. Cloned segments of the chicken c-ski proto-oncogene totaling 65 kilobases have been analyzed, and regions related to v-ski have been sequenced. The results indicate that v-ski is derived from at least five coding exons of c-ski, that it is correctly spliced, and that it is missing c-ski coding sequences at both its 5' and 3' ends. The c-ski and avian leukosis virus sequences that overlap the 5' virus/v-ski junction in Sloan-Kettering virus contain an 18-of-20-base sequence match that presumably played a role in the transduction of ski by facilitating virus/c-ski recombination.

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