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Structural enzymology of phosphate-t...

Lahiri, Sushmita Dipak.

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Structural enzymology of phosphate-transfer enzymes: Ground-state, intermediate, and transition-state analogue complexes.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Structural enzymology of phosphate-transfer enzymes: Ground-state, intermediate, and transition-state analogue complexes./
Author:	Lahiri, Sushmita Dipak.
Description:	185 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4820.
Contained By:	Dissertation Abstracts International64-10B.
Subject:	Biophysics, General. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3108150

Structural enzymology of phosphate-transfer enzymes: Ground-state, intermediate, and transition-state analogue complexes.
Lahiri, Sushmita Dipak.

Structural enzymology of phosphate-transfer enzymes: Ground-state, intermediate, and transition-state analogue complexes. - 185 p.

Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4820.

Thesis (Ph.D.)--Boston University, 2004.

The goal of this thesis is to understand the molecular mechanisms underlying enzyme-catalyzed phosphoryl-transfer reactions. X-ray crystallographic analysis was performed on members of the 2-L-haloacid dehalogenase (HAD) superfamily and on creatine kinase (guanidinum kinase family). These enzymes exemplify two different means of catalyzing this reaction type.Subjects--Topical Terms:

1019105
Biophysics, General.

Structural enzymology of phosphate-transfer enzymes: Ground-state, intermediate, and transition-state analogue complexes.
LDR:03576nmm 2200289 4500 001 1864968
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008 130614s2004 eng d
035 $a (UnM)AAI3108150
035 $a AAI3108150
040 $a UnM $c UnM
100 1 $a Lahiri, Sushmita Dipak. $3 1952432
245 1 0 $a Structural enzymology of phosphate-transfer enzymes: Ground-state, intermediate, and transition-state analogue complexes.
300 $a 185 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4820.
500 $a Major Professor: Karen N. Allen.
502 $a Thesis (Ph.D.)--Boston University, 2004.
520 $a The goal of this thesis is to understand the molecular mechanisms underlying enzyme-catalyzed phosphoryl-transfer reactions. X-ray crystallographic analysis was performed on members of the 2-L-haloacid dehalogenase (HAD) superfamily and on creatine kinase (guanidinum kinase family). These enzymes exemplify two different means of catalyzing this reaction type.
520 $a The HAD superfamily constitutes enzymes that catalyze C-Cl, C-P or O-P bond cleavage reactions. All members contain four highly conserved motifs; Motif I: DXDX[T/V][L/V], Motif II: [S/T]XX, Motif III: XX[K/R]XX, and Motif IV: K[G/S][D/S]XXX[D/N]. The first Asp in Motif I forms an acylphosphate enzyme intermediate in all phosphotransferase members of the superfamily. Two enzymes of the phosphotransferase subfamily were studied: phosphonoacetaldehyde hydrolase (phosphonatase) and beta-phosphoglucomutase (beta-PGM). Phosphonatase catalyzes the hydrolysis of phosphonoacetaldehyde to acetaldehyde and orthophosphate using an active site Lys53, to form a Schiff-base intermediate, and the active-site Asp nucleophile from Motif I, to form a phosphoenzyme intermediate. beta-PGM catalyzes the reversible conversion of beta-D-glucose 1-phosphate to beta-D-glucose 6-phosphate again utilizing the Asp nucleophile from Motif I to form a phosphoenzyme intermediate.
520 $a The structure determination of covalent reaction intermediates along with catalytically deficient phosphonatase mutants elucidate the roles of active-site residues involved in general acid/base catalysis in the bicovalent catalytic mechanism. The de novo structure of beta-PGM provided the first view of a stable phosphoaspartyl intermediate of HAD in the ground state. In addition, the beta-D-glucose-1,6 (bis)phosphate complex structure gave the first direct proof of a pentavalent phosphorane intermediate stabilized by an enzyme active site and confirmed the single nucleophile mechanism in beta-PGM.
520 $a Creatine kinase (CK) catalyzes the reversible phosphorylation of creatine. The structures of several isoforms of creatine kinase are available, none with the substrates/ligand bound. Here the first liganded structure of CK in complex with MgADP and with a transition-state analogue complex (MgADP-NO3-creatine) is described. In addition, structures of the substrate (AMP-PNP with creatine) and product (ADP plus phosphocyclocreatine) complexes show that two loops move considerably, to effectively close over the active site during catalysis. Together, these structures afford a direct view of the enzyme conformation along the entire reaction coordinate, linking protein dynamics with the chemistry of the reaction.
590 $a School code: 0017.
650 4 $a Biophysics, General. $3 1019105
690 $a 0786
710 2 0 $a Boston University. $3 1017454
773 0 $t Dissertation Abstracts International $g 64-10B.
790 1 0 $a Allen, Karen N., $e advisor
790 $a 0017
791 $a Ph.D.
792 $a 2004
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3108150