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1.
ACS Omega ; 5(23): 14069-14077, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32566873

RESUMO

Malabaricol is a unique plant natural product, 3-keto tricarbocyclic triterpenoid, isolated from Ailanthus malabarica. Malabaricol underwent reaction with aromatic aldehydes under alkaline conditions to form 2-arylidene analogs. Indoles and pyrazine ring system fused to the 2,3-position of malabaricol were synthesized. In this ring system of tricarbocyclic triterpenoid, the conformation is such that there is no steric hindrance due to C4 and C10 axial methyl groups and other skeletons. Malabaricol and its synthetic analogues show cytotoxic activity toward lung cancer, which was compared to that of standard doxorubicin.

2.
J Biol Chem ; 291(39): 20530-8, 2016 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-27484799

RESUMO

Amino-terminal acetylation is a critical co-translational modification of the newly synthesized proteins in a eukaryotic cell carried out by six amino-terminal acetyltransferases (NATs). All NATs contain at least one catalytic subunit, and some contain one or two additional auxiliary subunits. For example, NatE is a complex of Naa10, Naa50, and Naa15 (auxiliary). In the present study, the crystal structure of human Naa50 suggested the presence of CoA and acetylated tetrapeptide (AcMMXX) that have co-purified with the protein. Biochemical and thermal stability studies on the tetrapeptide library with variations in the first and second positions confirm our results from the crystal structure that a peptide with Met-Met in the first two positions is the best substrate for this enzyme. In addition, Naa50 acetylated all MXAA peptides except for MPAA. Transcriptome analysis of 10 genes that make up six NATs in humans from eight different cell lines suggests that components of NatE are transcribed in all cell lines, whereas others are variable. Because Naa10 is reported to acetylate all amino termini that are devoid of methionine and Naa50 acetylates all other peptides that are followed by methionine, we believe that NatE complex can be a major contributor for amino-terminal acetylation at the ribosome exit tunnel.


Assuntos
Acetiltransferase N-Terminal E/metabolismo , Oligopeptídeos/química , Biblioteca de Peptídeos , Células A549 , Acetilação , Células HEK293 , Humanos , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/genética , Especificidade por Substrato
3.
PLoS One ; 8(10): e75207, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24124477

RESUMO

Protein N-terminal methionine excision is an essential co-translational process that occurs in the cytoplasm of all organisms. About 60-70% of the newly synthesized proteins undergo this modification. Enzyme responsible for the removal of initiator methionine is methionine aminopeptidase (MetAP), which is a dinuclear metalloprotease. This protein is conserved through all forms of life from bacteria to human except viruses. MetAP is classified into two isoforms, Type I and II. Removal of the map gene or chemical inhibition is lethal to bacteria and to human cell lines, suggesting that MetAP could be a good drug target. In the present study we describe the discovery of a new genetic variant of the Type I MetAP that is present predominantly in the streptococci bacteria. There are two inserts (insert one: 27 amino acids and insert two: four residues) within the catalytic domain. Possible glycosylation and phosphorylation posttranslational modification sites are identified in the 'insert one'. Biochemical characterization suggests that this enzyme behaves similar to other MetAPs in terms of substrate specificity. Crystal structure Type Ia MetAP from Streptococcus pneumoniae (SpMetAP1a) revealed that it contains two molecules in the asymmetric unit and well ordered inserts with structural features that corroborate the possible posttranslational modification. Both the new inserts found in the SpMetAP1a structurally align with the P-X-X-P motif found in the M. tuberculosis and human Type I MetAPs as well as the 60 amino acid insert in the human Type II enzyme suggesting possible common function. In addition, one of the ß-hairpins within in the catalytic domain undergoes a flip placing a residue which is essential for enzyme activity away from the active site and the ß-hairpin loop of this secondary structure in the active site obstructing substrate binding. This is the first example of a MetAP crystallizing in the inactive form.


Assuntos
Metionil Aminopeptidases/metabolismo , Streptococcus/enzimologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Metionil Aminopeptidases/genética , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/fisiologia
4.
J Med Chem ; 56(13): 5295-305, 2013 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-23767698

RESUMO

Methionine aminopeptidases (MetAPs) are essential enzymes that make them good drug targets in cancer and microbial infections. MetAPs remove the initiator methionine from newly synthesized peptides in every living cell. MetAPs are broadly divided into type I and type II classes. Both prokaryotes and eukaryotes contain type I MetAPs, while eukaryotes have additional type II MetAP enzyme. Although several inhibitors have been reported against type I enzymes, subclass specificity is scarce. Here, using the fine differences in the entrance of the active sites of MetAPs from Mycobacterium tuberculosis , Enterococcus faecalis , and human, three hotspots have been identified and pyridinylpyrimidine-based molecules were selected from a commercial source to target these hotspots. In the biochemical evaluation, many of the 38 compounds displayed differential behavior against these three enzymes. Crystal structures of four selected inhibitors in complex with human MetAP1b and molecular modeling studies provided the basis for the binding specificity.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Metionil Aminopeptidases/antagonistas & inibidores , Pirimidinas/farmacologia , Sequência de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Domínio Catalítico , Cristalografia por Raios X , Enterococcus faecalis/enzimologia , Enterococcus faecalis/genética , Inibidores Enzimáticos/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Cinética , Metionil Aminopeptidases/química , Metionil Aminopeptidases/genética , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/genética , Ligação Proteica , Piridinas/química , Pirimidinas/química , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Estereoisomerismo
5.
Eur J Med Chem ; 45(11): 5208-16, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20832916

RESUMO

Designed novel imidazo[1,2-a]pyrazine based inhibitors, synthesized by condensing α-aminopyrazines with α-halocarbonyl compounds followed by electrophilic substitutions. Cytotoxic effects on four cancer cell lines evaluated. Based on preliminary data, imidazo[1,2-a]pyrazine template redesigned to improve activity.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
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