The <i>C. elegans</i> methionine aminopeptidase 2 analog <i>map‐2</i> is required for germ cell proliferation

Boxem, Mike; Tsai, Chiawei W.; Zhang, Yi; Saito, R. Mako; Liu, Jun O.

doi:10.1016/j.febslet.2004.08.077

Cited by 26 publications

(14 citation statements)

References 34 publications

(48 reference statements)

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“…These findings are consistent with the observation that MAP2 (p67) expression is inhibited in starved mammalian cell cultures and induced in proliferating cells (Gupta et al, 1997). Finally, MAP2 KD by RNAi caused germ cell proliferation defect in the worm Caenorhabditis elegans (Boxem et al, 2004).…”

Section: Map2s Versus Map1s: Overlapping or Redundant Functions In Hisupporting

confidence: 81%

Functional and Developmental Impact of Cytosolic Protein N-Terminal Methionine Excision in Arabidopsis

et al. 2005

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Protein N-terminal methionine (Met) excision (NME) is carried out by two types of Met aminopeptidases (MAPs), MAP1 and MAP2, in eukaryotes. Three enzymes, MAP1A, MAP2A, and MAP2B, have been identified in the cytoplasm of Arabidopsis (Arabidopsis thaliana). MAP transcript quantification revealed a predominance of MAP2B and developmental and organ-specific regulation of both MAP1A and MAP2s. By combining reverse genetics and reverse chemogenomics in transgenic plant lines, we have devised specific and reversible switches for the investigation of the role of cytoplasmic NME in Arabidopsis and of the respective contributions of the two types of cytoplasmic MAPs throughout development. dsRNA interference and knockout (KO) plant lines targeting either MAP1A alone or both MAP2s simultaneously were constructed and shown to display wild-type phenotypes. In the MAP1A KO context, modulating MAP2 activity by treatment with various concentrations of the specific drug fumagillin impaired plant development, with particularly strong effects on the root system. Reciprocally, complete MAP2 inhibition in various MAP1A knocked-down genetic backgrounds also generated a gradient of developmentally abnormal plants, but the effects on the root system were milder than in the KO context. In the absence of MAP2 activity, the severity of the phenotype in the MAP1A knocked-down lines was correlated to the extent of MAP1A mRNA accumulation. Complete cytoplasmic NME inactivation blocked development after plant germination. Thus, in plants, (1) cytoplasmic NME is essential; (2) MAP1A and MAP2s are functionally interchangeable, which is not the case in fungi and animals, as a complete block of either MAP-type activity does not cause any visible molecular or phenotypic effect; and (3) a minimal level of cytoplasmic MAP is required for normal development.

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Section: Map2s Versus Map1s: Overlapping or Redundant Functions In Hisupporting

confidence: 81%

Functional and Developmental Impact of Cytosolic Protein N-Terminal Methionine Excision in Arabidopsis

et al. 2005

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“…In budding yeast Saccharomyces cerevisiae, deletion of either ScMetAP1 or ScMetAP2 resulted in a slow-growth phenotype compared with the wild-type strain, whereas the double mutant is nonviable, indicating the redundant yet essential functions of both types of MetAP (1,2). In multicellular organisms MetAP2 has been shown to be essential for the proliferation and development of specific tissues (3,4).…”

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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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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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“…1). Methionine aminopeptidase activity is essential for cell growth in bacteria, fungi (1), and higher eukaryotes (2,3). However, methionine aminopeptidase cannot cleave N-formylated peptides (4).…”

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confidence: 99%

The Crystal Structure of Mitochondrial (Type 1A) Peptide Deformylase Provides Clear Guidelines for the Design of Inhibitors Specific for the Bacterial Forms

Fieulaine

Juillan-Binard

Serero

et al. 2005

Journal of Biological Chemistry

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Peptide deformylase (PDF) inhibitors have a strong potential to be used as a new class of antibiotics. However, recent studies have shown that the mitochondria of most eukaryotes, including humans, contain an essential PDF, PDF1A. The crystal structure of the Arabidopsis thaliana PDF1A (AtPDF1A), considered representative of PDF1As in general, has been determined. This structure displays several similarities to that of known bacterial PDFs. AtPDF1A behaves as a dimer, with the C-terminal residues responsible for linking the two subunits. This arrangement is similar to that of Leptospira interrogans PDF, the only other dimeric PDF identified to date. AtPDF1A is the first PDF for which zinc has been identified as the catalytic ion. However, the zinc binding pocket does not differ from the binding pockets of PDFs with iron rather than zinc. The crystal structure of AtPDF1A in complex with a substrate analog revealed that the substrate binding pocket of PDF1A displays strong modifications. The S1 binding pocket is significantly narrower, due to the creation of a floor from residues present in all PDF1As but not in bacterial PDFs. A true S3 pocket is created by the residues of a helical CD-loop, which is very long in PDF1As. Finally, these modified substrate binding pockets modify the position of the substrate in the active site. These differences provide guidelines for the design of bacterial PDF inhibitors that will not target mitochondrial PDFs.

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The C. elegans methionine aminopeptidase 2 analog map‐2 is required for germ cell proliferation

Cited by 26 publications

References 34 publications

Functional and Developmental Impact of Cytosolic Protein N-Terminal Methionine Excision in Arabidopsis

Functional and Developmental Impact of Cytosolic Protein N-Terminal Methionine Excision in Arabidopsis

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

The Crystal Structure of Mitochondrial (Type 1A) Peptide Deformylase Provides Clear Guidelines for the Design of Inhibitors Specific for the Bacterial Forms

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