Characterization of Full Length and Truncated Type I Human Methionine Aminopeptidases Expressed from <i>Escherichia coli</i>

Li, Jing Ya; Chen, Ling Ling; Cui, Yong; Luo, Qun; Gu, M.; Nan, Fa Jun; Ye, Qi Zhuang

doi:10.1021/bi0360859

Cited by 26 publications

(39 citation statements)

References 23 publications

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“…These compounds would then be used to assess the consequence of inhibition of HsMetAP1 on cell proliferation. Pyridine-2-carboxylic acid-amide derivatives, including compound 1, were previously reported to inhibit both the bacterial and yeast MetAP1 (13,14). We found this class of compounds has Ͼ100-fold selectivity for HsMetAP1 over HsMetAP2.…”

mentioning

confidence: 74%

“…Among the MetAP inhibitors reported, the pyridine-2-carboxylic acid thiazole-2-ylamide class has emerged as potent inhibitors of both E. coli and yeast MetAP1. Moreover, members of this class of compounds have been subsequently shown to inhibit recombinant HsMetAP1 (14,22). It remained unknown, however, whether this family of MetAP1 inhibitors also crossinteract with MetAP2.…”

Section: Discussionmentioning

confidence: 99%

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Elucidation of the function of type 1 human methionine aminopeptidase during cell cycle progression

Addlagatta

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Processing of the N-terminal initiator methionine is an essential cellular process conserved from prokaryotes to eukaryotes. The enzymes that remove N-terminal methionine are known as methionine aminopeptidases (MetAPs). Human MetAP2 has been shown to be required for the proliferation of endothelial cells and angiogenesis. The physiological function of MetAP1, however, has remained elusive. In this report we demonstrate that a family of inhibitors with a core structure of pyridine-2-carboxylic acid previously developed for the bacterial and yeast MetAP1 is also specific for human MetAP1 (HsMetAP1), as confirmed by both enzymatic assay and high-resolution x-ray crystallography. Treatment of tumor cell lines with the MetAP1-specific inhibitors led to an accumulation of cells in the G2͞M phase, suggesting that HsMetAP1 may play an important role in G2͞M phase transition. Overexpression of HsMetAP1, but not HsMetAP2, conferred resistance of cells to the inhibitors, and the inhibitors caused retention of N-terminal methionine of a known MetAP substrate, suggesting that HsMetAP1 is the cellular target for the inhibitors. In addition, when HsMetAP1 was knocked down by gene-specific siRNA, cells exhibited slower progression during G2͞M phase, a phenotype similar to cells treated with MetAP1 inhibitors. Importantly, MetAP1 inhibitors were able to induce apoptosis of leukemia cell lines, presumably as a consequence of their interference with the G2͞M phase checkpoint. Together, these results suggest that MetAP1 plays an important role in G2͞M phase of the cell cycle and that it may serve as a promising target for the discovery and development of new anticancer agents.aminopeptidase inhibitors ͉ angiogenesis ͉ apoptosis

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mentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Elucidation of the function of type 1 human methionine aminopeptidase during cell cycle progression

Addlagatta

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, compound ( 42 ) was found to be less active against Hs MetAP1 (IC 50 = 10.4 μM; Co(II) cofactors), than Ec MetAP1 (Table 4 ) [63]. Although ( 42 ) only exhibits a two-fold increase in activity favoring the bacterial isoform, the incorporation of lipophilic amide functionalities at the 3 position of the picolinamide scaffold affords compounds inactive against Hs MetAPs.…”

Section: Classes Of Metap Inhibitorsmentioning

confidence: 99%

Advances in Bacterial Methionine Aminopeptidase Inhibition

Helgren¹,

Wangtrakuldee²,

Staker³

et al. 2015

CTMC

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Methionine aminopeptidases (MetAPs) are metalloenzymes that cleave the N-terminal methionine from newly synthesized peptides and proteins. These MetAP enzymes are present in bacteria, and knockout experiments have shown that MetAP activity is essential for cell life, suggesting that MetAPs are good antibacterial drug targets. MetAP enzymes are also present in the human host and selectivity is essential. There have been significant structural biology efforts and over 65 protein crystal structures of bacterial MetAPs are deposited into the PDB. This review highlights the available crystallographic data for bacterial MetAPs. Structural comparison of bacterial MetAPs with human MetAPs highlights differences that can lead to selectivity. In addition, this review includes the chemical diversity of molecules that bind and inhibit the bacterial MetAP enzymes. Analysis of the structural biology and chemical space of known bacterial MetAP inhibitors leads to a greater understanding of this antibacterial target and the likely development of potential antibacterial agents.

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“…The 2 zebrafish proteins also shared the putative zinc finger-and cobaltcoordinating residues (supplemental Figure 1). 31 …”

Section: Metaps Were Highly Conservedmentioning

confidence: 99%

Methionine aminopeptidase 2 is required for HSC initiation and proliferation

Alvin¹,

Fung²,

Lin³

et al. 2011

Blood

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In a chemical screening, we tested the antiangiogenic effects of fumagillin derivatives and identified fumagillin as an inhibitor of definitive hematopoiesis in zebrafish embryos. Fumagillin is known to target methionine aminopeptidase II (MetAP2), an enzyme whose function in hematopoiesis is unknown. We investigated the role of MetAP2 in hematopoiesis by using zebrafish embryo and human umbilical cord blood models. Zebrafish metap2 was expressed ubiquitously during early embryogenesis and later in the somitic region, the caudal hematopoietic tissue, and pronephric duct. metap2 was inhibited by morpholino and fumagillin treatment, resulting in increased mpo expression at 18 hours postfertilization and reduced c-myb expression along the ventral wall of dorsal aorta at 36 hours postfertilization. It also disrupted intersegmental vessels in Tg-(fli1:gfp) embryos without affecting development of major axial vasculatures. Inhibition of MetAP2 in CB CD34 ؉ cells by fumagillin had no effect on overall clonogenic activity but significantly reduced their engraftment into immunodeficient nonobese diabetes/severe combined immunodeficiency mice.

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Characterization of Full Length and Truncated Type I Human Methionine Aminopeptidases Expressed from Escherichia coli

Cited by 26 publications

References 23 publications

Elucidation of the function of type 1 human methionine aminopeptidase during cell cycle progression

Elucidation of the function of type 1 human methionine aminopeptidase during cell cycle progression

Advances in Bacterial Methionine Aminopeptidase Inhibition

Methionine aminopeptidase 2 is required for HSC initiation and proliferation

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