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Ligand binding in human inosine 5'-m...

Risal, Dipesh.

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Ligand binding in human inosine 5'-monophosphate dehydrogenase type I and type II: Crystallographic and kinetic studies.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Ligand binding in human inosine 5'-monophosphate dehydrogenase type I and type II: Crystallographic and kinetic studies./
Author:	Risal, Dipesh.
Description:	146 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0108.
Contained By:	Dissertation Abstracts International64-01B.
Subject:	Biophysics, General. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3078417
ISBN:	0493989412

Ligand binding in human inosine 5'-monophosphate dehydrogenase type I and type II: Crystallographic and kinetic studies.
Risal, Dipesh.

Ligand binding in human inosine 5'-monophosphate dehydrogenase type I and type II: Crystallographic and kinetic studies. - 146 p.

Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0108.

Thesis (Ph.D.)--The University of Rochester, 2003.

IMPDH catalyzes the NAD-dependent oxidation of inosine 5' -monophosphate (IMP) to xanthosine 5'-monophosphate. Effective drugs against this attractive anti-cancer target would specifically inhibit the inducible type II isoform, while leaving the type I isoform unaffected for 'housekeeping' production of guanine nucleotides. This study reports binding interactions between four ligands and the human enzymes inosine 5'-monophosphate dehydrogenase (IMPDH) type I and type II characterized by X-ray crystallography and enzyme kinetic studies.

ISBN: 0493989412Subjects--Topical Terms:

1019105
Biophysics, General.

Ligand binding in human inosine 5'-monophosphate dehydrogenase type I and type II: Crystallographic and kinetic studies.
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035 $a AAI3078417
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100 1 $a Risal, Dipesh. $3 1948122
245 1 0 $a Ligand binding in human inosine 5'-monophosphate dehydrogenase type I and type II: Crystallographic and kinetic studies.
300 $a 146 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0108.
500 $a Supervisor: Barry M. Goldstein.
502 $a Thesis (Ph.D.)--The University of Rochester, 2003.
520 $a IMPDH catalyzes the NAD-dependent oxidation of inosine 5' -monophosphate (IMP) to xanthosine 5'-monophosphate. Effective drugs against this attractive anti-cancer target would specifically inhibit the inducible type II isoform, while leaving the type I isoform unaffected for 'housekeeping' production of guanine nucleotides. This study reports binding interactions between four ligands and the human enzymes inosine 5'-monophosphate dehydrogenase (IMPDH) type I and type II characterized by X-ray crystallography and enzyme kinetic studies.
520 $a The crystal structure of the type II isoform with the first crystallographically observed bound NAD is presented in Chapter 2. This structure reveals important interactions between the NAD carboxamide group and active site residues and further demonstrates the flexibility of the active-site loop in accommodating non-native ligands.
520 $a The first crystal structure of human IMPDH type I is reported in Chapter 3. This structure confirms the general structural similarity between the two isoforms in the active site region. This similarity is an important prerequisite for any drug design program with type II-specificity as a goal.
520 $a Mycophenolic Acid (MPA) is a successful immunosuppressive agent but is ineffective as an anticancer agent. C2-MAD is a hybrid compound with the 'head' of MPA attached to the adenosine 'tail' portion of NAD in an attempt to improve on the bioavailability of MPA. The crystal structure of IMPDH type II with C2-MAD bound is presented in Chapter 4. This structure shows that the MPA 'head' of C2-MAD binds much like MPA while the adenosine 'tail' interacts much like an NAD analog previously studied, revealing that the two subsites can be coupled in a single inhibitor. Further, the C2-MAD and NAD-bound structures reveal that dinucleotide binding only partially orders the active site 'flap'. The existing hypothesis that dinucleotide binding orders the flap therefore needs to be revised in light of these findings. The first available enzyme-bound conformation of ribavirin monophosphate, an important immunosuppressive agent, is also described in Chapter 4, and a putative ion-binding site is identified.
520 $a Appendix A describes the kinetic results of a set of novel compounds that are modifications of MPA and are the result of several rounds of structure-aided drug design.
590 $a School code: 0188.
650 4 $a Biophysics, General. $3 1019105
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Chemistry, Pharmaceutical. $3 550957
690 $a 0786
690 $a 0307
690 $a 0491
710 2 0 $a The University of Rochester. $3 1249304
773 0 $t Dissertation Abstracts International $g 64-01B.
790 1 0 $a Goldstein, Barry M., $e advisor
790 $a 0188
791 $a Ph.D.
792 $a 2003
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3078417