NDLI: One substrate, five products: reactions catalyzed by the dihydroneopterin aldolase from Mycobacterium tuberculosis

Content Provider	PubMed Central
Author	Czekster, Clarissa M. Blanchard, John S.
Abstract	Tetrahydrofolate cofactors are required for one carbon transfer reactions involved in the synthesis of purines, amino acids, and thymidine. Inhibition of tetrahydrofolate biosynthesis is a powerful therapeutic strategy in the treatment of several diseases, and the possibility of using antifolates to inhibit enzymes from Mycobacterium tuberculosis has been explored. This work focuses on the study of the first enzyme in tetrahydrofolate biosynthesis that is unique to bacteria, dihydroneopterin aldolase (MtDHNA). This enzyme requires no metals or cofactors, and does not form a protein mediated Schiff base with the substrate, unlike most aldolases. Here, we were able to demonstrate that the reaction catalyzed by MtDHNA generates three different pterin products, one of which is not produced by other wild type DHNAs. The enzyme-substrate complex partitions 51% in the first turnover to form the aldolase product, 24% to the epimerase product, and 25% to the oxygenase product. The aldolase reaction is strongly pH-dependent, and apparent pK a values were obtained for the first time for this class of enzyme. Furthermore, chemistry is rate-limiting for the aldolase reaction, and the analysis of solvent kinetic isotope effects in steady-state and pre-steady-state conditions, combined with proton inventory studies revealed that two protons and a likely solvent contribution are involved in formation and breakage of a common intermediate. This study provides information about the plasticity required from a catalyst that possesses high substrate specificity while being capable of utilizing two distinct epimers with the same efficiency to generate five distinct products.
Related Links	http://dx.doi.org/10.1021/ja308350f
Ending Page	19771
Page Count	14
Starting Page	19758
File Format	PDF
ISSN	15205126
e-ISSN	15205126
Journal	Journal of the American Chemical Society
Issue Number	48
Volume Number	134
Language	English
Publisher Date	2012-12-05
Access Restriction	Open
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Chemistry Colloid and Surface Chemistry Biochemistry Catalysis

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

EnzymeArchitecture: Remarkably Similar TransitionStates for Triosephosphate Isomerase-Catalyzed Reactions of the WholeSubstrate and the Substrate in Pieces

Asymmetric Petasis Reactions Catalyzed by Chiral Biphenols

Edaxadiene: A New Bioactive Diterpene from Mycobacterium tuberculosis

Edaxadiene: A New Bioactive Diterpene from Mycobacterium tuberculosis

Probing the Mechanism of 1,4-Conjugate Elimination Reactions Catalyzed by Terpene Synthases

Characterizationof a Cross-Linked Protein–NucleicAcid Substrate Radical in the Reaction Catalyzed by RlmN

Aspartate-Catalyzed Asymmetric Epoxidation Reactions

Gold(I)-Catalyzed Enantioselective Polycyclization Reactions

Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed Amino Acid

One substrate, five products: reactions catalyzed by the dihydroneopterin aldolase from Mycobacterium tuberculosis

Similar Documents

EnzymeArchitecture: Remarkably Similar TransitionStates for Triosephosphate Isomerase-Catalyzed Reactions of the WholeSubstrate and the Substrate in Pieces

Asymmetric Petasis Reactions Catalyzed by Chiral Biphenols

Edaxadiene: A New Bioactive Diterpene from Mycobacterium tuberculosis

Edaxadiene: A New Bioactive Diterpene from Mycobacterium tuberculosis

Probing the Mechanism of 1,4-Conjugate Elimination Reactions Catalyzed by Terpene Synthases

Characterizationof a Cross-Linked Protein–NucleicAcid Substrate Radical in the Reaction Catalyzed by RlmN

Aspartate-Catalyzed Asymmetric Epoxidation Reactions

Gold(I)-Catalyzed Enantioselective Polycyclization Reactions

Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed Amino Acid

One substrate, five products: reactions catalyzed by the dihydroneopterin aldolase from Mycobacterium tuberculosis