Advanced search options

Advanced Search Options 🞨

Browse by author name (“Author name starts with…”).

Find ETDs with:

in
/  
in
/  
in
/  
in

Written in Published in Earliest date Latest date

Sorted by

Results per page:

Sorted by: relevance · author · university · dateNew search

You searched for subject:(Dimethylarginine dimethylaminohydrolase). Showing records 1 – 3 of 3 total matches.

Search Limiters

Last 2 Years | English Only

No search limiters apply to these results.

▼ Search Limiters


University of Texas – Austin

1. -9758-983X. The design of halopyridine-based activity-based probes and mechanistic studies of succinylarginine dihydrolase.

Degree: PhD, Pharmaceutical Sciences, 2015, University of Texas – Austin

An important design aspect of covalent inactivators is the balance between reactivity, or reversibility of reaction, with nucleophiles in solution and reactivity with nucleophiles at a targeted protein site. We previously identified 4-halopyridines as fragment-sized covalent inactivators of the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Binding of these inactivators stabilizes the more reactive pyridinium form while the less reactive neutral form predominates in solution. Herein, we demonstrate that simple 2- and 4-chloropyridines are extensible as covalent modifiers of other proteins within the E. coli proteome, that halogen positioning can impart target selectivity, and that the targets include a subset of Cys-containing purine binding sites. As one specific example, inosine-5’-monophosphate dehydrogenase is shown to be labeled by a 2-chloropyridine at a catalytic Cys305 residue within the inosine binding site. These results indicate that a simple 2- or 4-chloropyridine core can have wider application as a warhead for incorporation into covalent inhibitors of proteins with diverse function. N-succinylarginine dihydrolase (AstB), like DDAH and arginine deiminase, is part of the amidinotransferase (AT) superfamily. AstB shows conservation of the catalytic residues and carries out a similar type of reaction as other hydrolases in the AT superfamily. Herein, we report the mechanistic studies of AstB and provide insights into how this enzyme performs its dihydrolase activity instead of a “mono” hydrolase reaction, which is more prevalent in this superfamily. Advisors/Committee Members: Fast, Walter L. (advisor), Whitman, Christian P (committee member), Lee, Seongmin (committee member), Liu, Hung-wen (committee member), Iverson, Brent L (committee member).

Subjects/Keywords: Dimethylarginine dimethylaminohydrolase; Halopyridine; Activity-based probes; Succinylarginine dihydrolase

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

-9758-983X. (2015). The design of halopyridine-based activity-based probes and mechanistic studies of succinylarginine dihydrolase. (Doctoral Dissertation). University of Texas – Austin. Retrieved from http://hdl.handle.net/2152/46556

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Chicago Manual of Style (16th Edition):

-9758-983X. “The design of halopyridine-based activity-based probes and mechanistic studies of succinylarginine dihydrolase.” 2015. Doctoral Dissertation, University of Texas – Austin. Accessed October 20, 2019. http://hdl.handle.net/2152/46556.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

MLA Handbook (7th Edition):

-9758-983X. “The design of halopyridine-based activity-based probes and mechanistic studies of succinylarginine dihydrolase.” 2015. Web. 20 Oct 2019.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Vancouver:

-9758-983X. The design of halopyridine-based activity-based probes and mechanistic studies of succinylarginine dihydrolase. [Internet] [Doctoral dissertation]. University of Texas – Austin; 2015. [cited 2019 Oct 20]. Available from: http://hdl.handle.net/2152/46556.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Council of Science Editors:

-9758-983X. The design of halopyridine-based activity-based probes and mechanistic studies of succinylarginine dihydrolase. [Doctoral Dissertation]. University of Texas – Austin; 2015. Available from: http://hdl.handle.net/2152/46556

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

2. Linsky, Thomas W. Studies on the mechanism and inhibition of enzymes in the pentein superfamily.

Degree: PhD, Biochemistry, 2012, University of Texas – Austin

Dimethylarginine dimethylaminohydrolase (DDAH) indirectly regulates nitric oxide production by hydrolyzing methylated arginines, which are endogenous nitric oxide synthase inhibitors. This enzyme is a member of the mechanistically diverse pentein superfamily, which contains hydrolase, dihydrolase, and amidinotransferase enzymes. These enzymes are proposed to use the same first catalytic step, followed by partitioning into their respective activities. Here, variants of DDAH that can catalyze the dihydrolase and amidinotransfer reactions are presented, as well as a variant of succinylarginine dihydrolase which catalyzes a single hydrolysis reaction. The results experimentally demonstrate that the proposed common catalytic intermediate can be used for several different reactions. The results suggest that enzymes in the pentein superfamily may have evolved divergently from a catalytically promiscuous ancestor. The control DDAH asserts over nitric oxide production makes it an attractive drug target for disease states marked by pathological overproduction of nitric oxide. Only a limited number of inhibitors different from substrate are reported, due in part to lack of robust assays for high-throughput screening of compound libraries. Therefore, high-throughput assays were developed, optimized, and validated to screen for inhibitors of Pseudomonas aeruginosa DDAH and human DDAH-1. These assays were used to screen three commercial libraries totaling 6,466 compounds. One drug in phase III clinical trials, ebselen, was identified and characterized as a bioavailable, rapid covalent inactivator of DDAH both in vitro and in cultured cells. Four "fragment-sized" inhibitors were also identified and characterized in the screening, including 4-halopyridines and benzimidazole-like compounds. The 4-halopyridines, not previously known to modify proteins, act as quiescent affinity labels to selectively inactivate DDAH, and the benzimidazole-like compounds are competitive, rapidly reversible inhibitors of DDAH. These diverse molecules serve as starting points for the development of molecular probes and therapeutic drugs to reduce pathological overproduction of nitric oxide. Advisors/Committee Members: Fast, Walter L. (advisor).

Subjects/Keywords: Dimethylarginine dimethylaminohydrolase; Succinylarginine dihydrolase; Pentein; High-throughput screening

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Linsky, T. W. (2012). Studies on the mechanism and inhibition of enzymes in the pentein superfamily. (Doctoral Dissertation). University of Texas – Austin. Retrieved from http://hdl.handle.net/2152/22148

Chicago Manual of Style (16th Edition):

Linsky, Thomas W. “Studies on the mechanism and inhibition of enzymes in the pentein superfamily.” 2012. Doctoral Dissertation, University of Texas – Austin. Accessed October 20, 2019. http://hdl.handle.net/2152/22148.

MLA Handbook (7th Edition):

Linsky, Thomas W. “Studies on the mechanism and inhibition of enzymes in the pentein superfamily.” 2012. Web. 20 Oct 2019.

Vancouver:

Linsky TW. Studies on the mechanism and inhibition of enzymes in the pentein superfamily. [Internet] [Doctoral dissertation]. University of Texas – Austin; 2012. [cited 2019 Oct 20]. Available from: http://hdl.handle.net/2152/22148.

Council of Science Editors:

Linsky TW. Studies on the mechanism and inhibition of enzymes in the pentein superfamily. [Doctoral Dissertation]. University of Texas – Austin; 2012. Available from: http://hdl.handle.net/2152/22148


Wayne State University

3. Nasser, Samar Abdulla. Effect Of Dimethylarginine Dimethylaminohydrolase In The Development Of Salt Sensitivity.

Degree: PhD, Physiology, 2011, Wayne State University

Salt sensitivity is associated with a rise in blood pressure (BP) occurring during sodium loading and/or a fall in BP during sodium restriction that exceeds random fluctuations in BP. Salt sensitivity is more common in African American than Caucasian hypertensives and is also present, in normotensive African Americans. The mechanism or mechanisms resulting in salt-sensitive hypertension are multiple and include both activation of the renin angiotensin system via increases in angiotensin II and reductions in the endogenous vasodilator, nitric oxide (NO). An important means of NO downregulation is through asymmetric dimethylarginine (ADMA), an endogenous NO inhibitor, which is largely metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The activity of DDAH is impaired by oxidative stress, thereby permitting ADMA to accumulate thus resulting in further inhibition of NO. Increases in oxidative stress, reduction in DDAH activity, and augmented action of ADMA on depressing NO production represents a plausible mechanism in human salt sensitivity. The study investigates and characterizes the above mechanism through which salt-induced depression of NO synthesis occurs in normotensive African Americans. The study population was a cohort of mostly young (mean age 45 years, SD = 6.0), female (87%), African Americans who were normotensive, and overweight. The DDAH level and NO metabolites came down after sodium exposure (6.17% and 11.53%, respectively), while the BP rose (SBP: +2.8 mm Hg; DBP +0.8 mm Hg) and the augmentation index (a measure of arterial stiffness) increased by almost 12% after sodium exposure, though not statistically significant. The difference in sodium:creatinine ratio was directly proportional to the change in BP (SBP: p = 0.01; DBP p = 0.13), which likely mediated the BP effect. Additionally, NO metabolites and DDAH levels were positively correlated to each other (r = 0.90; p = 0.0001), and changes in both DDAH and NO levels were negatively correlated to changes in augmentation index (DDAH: r = -0.61; p = 0.04; NO: r = -0.59; p = 0.05). As expected, the DDAH and NO levels increased while the augmentation index decreased reflecting a reduction in arterial stiffness. Overall, in a cohort of young, overweight, African American normotensive women, sodium exposure was directly proportional to the difference in BP and there was a reduction in DDAH level and NO metabolites, with significant indirect correlations between DDAH, NO, and augmentation index. Despite lack of significance in the differences of DDAH, ADMA, and NO between the treatment groups, the combined group results trended in the direction of the central hypothesis that increased dietary sodium intake downregulates DDAH and depresses NO production, resulting in a rise in BP and vascular stiffness. This initial study is the first demonstrating the trend that increased sodium intake was associated with a reduction in DDAH activity, and a depression in NO metabolites in healthy, normotensive African Americans. Advisors/Committee Members: John M. Flack.

Subjects/Keywords: African American; asymmetric dimethylarginine; blood pressure; dimethylarginine dimethylaminohydrolase; nitric oxide; salt sensitivity; Medicine and Health Sciences; Physiology

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Nasser, S. A. (2011). Effect Of Dimethylarginine Dimethylaminohydrolase In The Development Of Salt Sensitivity. (Doctoral Dissertation). Wayne State University. Retrieved from https://digitalcommons.wayne.edu/oa_dissertations/202

Chicago Manual of Style (16th Edition):

Nasser, Samar Abdulla. “Effect Of Dimethylarginine Dimethylaminohydrolase In The Development Of Salt Sensitivity.” 2011. Doctoral Dissertation, Wayne State University. Accessed October 20, 2019. https://digitalcommons.wayne.edu/oa_dissertations/202.

MLA Handbook (7th Edition):

Nasser, Samar Abdulla. “Effect Of Dimethylarginine Dimethylaminohydrolase In The Development Of Salt Sensitivity.” 2011. Web. 20 Oct 2019.

Vancouver:

Nasser SA. Effect Of Dimethylarginine Dimethylaminohydrolase In The Development Of Salt Sensitivity. [Internet] [Doctoral dissertation]. Wayne State University; 2011. [cited 2019 Oct 20]. Available from: https://digitalcommons.wayne.edu/oa_dissertations/202.

Council of Science Editors:

Nasser SA. Effect Of Dimethylarginine Dimethylaminohydrolase In The Development Of Salt Sensitivity. [Doctoral Dissertation]. Wayne State University; 2011. Available from: https://digitalcommons.wayne.edu/oa_dissertations/202

.