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Chemistry and biology of human methi...

Hu, Xiaoyi.

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Chemistry and biology of human methionine aminopeptidases.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Chemistry and biology of human methionine aminopeptidases./
Author:	Hu, Xiaoyi.
Description:	131 p.
Notes:	Adviser: Jun O. Liu.
Contained By:	Dissertation Abstracts International68-04B.
Subject:	Chemistry, Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3262435

Chemistry and biology of human methionine aminopeptidases.
Hu, Xiaoyi.

Chemistry and biology of human methionine aminopeptidases. - 131 p.

Adviser: Jun O. Liu.

Thesis (Ph.D.)--The Johns Hopkins University, 2007.

Chemical biology has not only advanced our understanding of the function of human methionine aminopeptidases in mammalian cell proliferation, but has also uncovered potential therapeutic compounds.Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

Chemistry and biology of human methionine aminopeptidases.
LDR:04278nam 2200325 a 45 001 938922
005 20110512
008 110512s2007 eng d
035 $a (UMI)AAI3262435
035 $a AAI3262435
040 $a UMI $c UMI
100 1 $a Hu, Xiaoyi. $3 1262893
245 1 0 $a Chemistry and biology of human methionine aminopeptidases.
300 $a 131 p.
500 $a Adviser: Jun O. Liu.
500 $a Source: Dissertation Abstracts International, Volume: 68-04, Section: B, page: 2277.
502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2007.
520 $a Chemical biology has not only advanced our understanding of the function of human methionine aminopeptidases in mammalian cell proliferation, but has also uncovered potential therapeutic compounds.
520 $a Protein translation starts with a methionine residue in eukaryotes, or formylated methionine in prokaryotes. A significant number of newly translated proteins have their initiating methionines removed for further post-translational modifications. Processing of the N-terminal methionine is conserved from prokaryotes to eukaryotes, and has been demonstrated to be essential for cell proliferation and viability. The enzymes that remove the N-terminal methionine are known as methionine aminopeptidases (MetAPs). They are metalloproteases with CO 2+-dependent activity in vitro. There are two types of MetAPs, MetAP1 and MetAP2, in eukaryotic cells with distinct N -terminal domains. In human, MetAP2 has been identified as the physiological target of the anti-angiogenic compound, fumagillin. Further biophysical and pharmacological studies have demonstrated MetAP2 as anti-cancer therapeutic target.
520 $a In contrast to MetAP2, little was known about the functions of MetAP1 in mammalian cells. To identify isoform-specific inhibitors, I have conducted high throughput screening of a 175,000-compound library. One family of inhibitors found contains the non-peptidic core structure of pyridinyl pyrimidines. In vivo substrate processing and structural analysis of the enzyme-inhibitor complexes have revealed that these compounds are non-selective inhibitors for human MetAPs.
520 $a Using metal-chelating pyridine-2-carboxylates, which were previously identified as E. coli and yeast MetAP1 inhibitors, we demonstrated that MetAP1-specific inhibition could delay cell cycle progression at G 2/M phase. This eventually caused cellular apoptosis in leukemia and lymphoma cell lines. X-ray crystallographic studies of the enzyme-inhibitor complexes revealed a unique mechanism of inhibition in which one additional metal ion is coordinated by inhibitor in the enzyme active site, therefore, preventing substrate accessibility.
520 $a Bengamides, a family of non-selective inhibitors for MetAPs, were used to study the physiologically-relevant substrate(s) involved in cell cycle regulations. The non-receptor tyrosine kinase, c-Src, was found to be processed by MetAPs. Inhibition by bengamide increased the c-Src N-terminal methionine level while decreased its N-terminal myristoylation. The subcellular distribution of c-Src was consequently shifted from the plasma membrane to the cytosol. Furthermore, bengamide A decreased the tyrosine kinase activities of c-Src both in vitro and in vivo, and eventually delaying cell cycle progression at G2/M phase. These results indicated that c-Src is a physiologically-relevant substrate of MetAP, the dysfunction of which is likely to account for the cell cycle effects of MetAP inhibitors.
520 $a A mitochondrial MetAP (MetAP1D) has recently been reported for human beings. Its gene was successfully cloned and recombinantly expressed in E. coli. Biochemical characterization of MetAP1D suggested its Co 2+-dependence for enzyme activity. Positive cooperativity has been detected for the enzyme activation by the binding of metal ions. Kinetic studies indicated the catalytic activity for MetAP1D is 100-fold lower than cytosolic MetAP1 and MetAP2.
590 $a School code: 0098.
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0419
690 $a 0487
710 2 0 $a The Johns Hopkins University. $3 1017431
773 0 $t Dissertation Abstracts International $g 68-04B.
790 $a 0098
790 1 0 $a Liu, Jun O., $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3262435