Congratulations Dr. Harishchandra Subedi

Dr. Subedi
Join us to congratulate Dr. Harishchandra Subedi for completing his PhD from Kent State University, Kent, Ohio, USA and joining a faculty position at  Kent State University, Tuscarawas campus, New Philadelphia Ohio.

Dr. Subedi worked with Prof. Nicola E. Brasch on kinetic and mechanistic studies on the reactions of vitamin B12 (cobalamin) complexes with the nitroxyl (HNO) donors for his PhD.

Check out Dr. Subedi's google scholar profile for his publications.

Here is a synopsis of his research work:

Nitric oxide (NO, ·NO) is a gaseous messenger molecule produced in cells from L–arginine by nitric oxide synthases. The chemical and biological properties of NO have been extensively studied for well over a decade. However, recent studies have shown that nitroxyl (nitrosyl hydride, HNO), the one–electron–reduction product of NO, may also be formed in biological systems, from the oxidation of L–arginine by nitric oxide synthase, particularly in the absence of tetrahydrobiopterin cofactor. It has also been demonstrated that HNO has biological activity and chemical reactivity distinct from ·NO. Much less is known about the reactivity of HNO, including its reactivity with transition metal complexes. A fundamental understanding of this is important, given that about one third of proteins are metalloproteins.

His dissertation work presented the first studies on the reaction between an HNO donor compound and vitamin B12 complexes. Detailed kinetic and mechanistic studies have been carried out on the reactions of two well characterized HNO donors, Angeli’s salt (AS) and Piloty’s acid (PA), with cobalamins (vitamin B12 derivatives). Cobalamins have important role as cofactors in two B12–dependent enzymatic reactions in humans. Furthermore cobalamins have three readily accessible oxidation states (Co3+, Co2+ and Co+). 

Although it is well established that HNO reduces transition metals including transition metal centers of porphyrins and metalloproteins, oxidation of a transition metal center by HNO is, to our knowledge, unprecedented. Importantly, results from kinetic measurements suggest that HNO can oxidize Co(I) center of cob(I)alamin. Given the abundance of metals in biological systems in addition to about one–third of proteins being metalloproteins, these results may have important implications in regards to elucidating the potential roles and toxicity of HNO in biological systems.

Studies by others suggest that the reduced vitamin B12 complex, cob(II)alamin, scavenges nitric oxide to form air–sensitive nitroxylcobalamin (NOCbl) in vivo. The fate of newly formed NOCbl is not known. A detailed mechanistic investigation of the oxidation of NOCbl by oxygen is presented. Only base–on NOCbl reacts with O2, and the reaction proceeds via an associative mechanism involving a peroxynitritocob(III)alamin intermediate, Co(III)–N(O)OO. The intermediate undergoes O−O bond homolysis and ligand isomerization to ultimately yield nitrocobalamin (NO2Cbl) and aquacobalamin (H2OCbl+/HOCbl), respectively. Ligand isomerization may potentially occur independent of O−O bond homolysis. Formation of OH and NO2 intermediates from O−O bond homolysis is demonstrated using phenol and tyrosine radical traps and the characterization of small amounts of a corrinoid product with minor modifications to the corrin ring.