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Zhu W.,Shandong University | Liu Y.,Shandong University | Liu Y.,CAS Northwest Institute of Plateau Biology
ACS Catalysis | Year: 2015

7-Carboxy-7-deazaguanine synthase (QueE) is a radical S-adenosylmethionine (SAM) enzyme that catalyzes the conversion of 6-carboxy-5,6,7,8-tetrahydropterin (CPH4) to 7-carboxy-7-deazaguanine (CDG). QueE also shows a clear dependence on Mg2+ ion and is considered a new feature for a radical SAM enzyme. The catalytic mechanism of QueE from B. multivorans has been studied using a combined quantum mechanics and molecular mechanics (QM/MM) method. The results of our calculations reveal that the key ring-contraction step involves a bridged intermediate rather than a ring-opening one. For the QueE-Mg2+ system, the elimination of ammonia is calculated to be rate limiting with a free energy barrier of 18.8 kcal/mol, which is basically in accordance with the estimated value (20.9 kcal/mol) from the experiment. For QueE-Na+ complex, the rate-limiting step switches to the formation of the bridged intermediate with an energy barrier of 29.3 kcal/mol. Natural population analysis indicates that the metal ions do not act as Lewis acids; therefore, they mainly play a role in fixing the substrate in its reactive conformation. The different coordination of Mg2+ and Na+ with the substrate is suggested to be the main reason for leading to the different activities of QueE-Mg2+ and QueE-Na+ complexes. © 2015 American Chemical Society. Source


Sheng X.,Shandong University | Liu Y.,Shandong University | Liu Y.,CAS Northwest Institute of Plateau Biology
Organic and Biomolecular Chemistry | Year: 2014

Nicotinamidase (Pnc1) is a member of Zn-dependent amidohydrolases that hydrolyzes nicotinamide (NAM) to nicotinic acid (NA), which is a key step in the salvage pathway of NAD+ biosynthesis. In this paper, the catalytic mechanism of Pnc1 has been investigated by using a combined quantum-mechanical/ molecular-mechanical (QM/MM) approach based on the recently obtained crystal structure of Pnc1. The reaction pathway, the detail of each elementary step, the energetics of the whole catalytic cycle, and the roles of key residues and Zn-binding site are illuminated. Our calculation results indicate that the catalytic water molecule comes from the bulk solvent, which is then deprotonated by residue D8. D8 functions as a proton transfer station between C167 and NAM, while the activated C167 serves as the nucleophile. The residue K122 only plays a role in stabilizing intermediates and transition states. The oxyanion hole formed by the amide backbone nitrogen atoms of A163 and C167 has the function to stabilize the hydroxyl anion of nicotinamide. The Zn-binding site rather than a single Zn2+ ion acts as a Lewis acid to influence the reaction. Two elementary steps, the activation of C167 in the deamination process and the decomposition of catalytic water in the hydrolysis process, correspond to the large energy barriers of 25.7 and 28.1 kcal mol-1, respectively, meaning that both of them contribute a lot to the overall reaction barrier. Our results may provide useful information for the design of novel and efficient Pnc1 inhibitors and related biocatalytic applications. © 2014 The Royal Society of Chemistry. Source


Sheng X.,Shandong University | Liu Y.,Shandong University | Liu Y.,CAS Northwest Institute of Plateau Biology
Biochemistry | Year: 2013

Pyruvate dehydrogenase multienzyme complex (PDHc) is a member of a family of 2-oxo acid dehydrogenase (OADH) multienzyme complexes involved in several central points of oxidative metabolism, and the E1 subunit is the most important component in the entire PDHc catalytic system, which catalyzes the reversible transfer of an acetyl group from a pyruvate to the lipoyl group of E2 subunit lipoly domain. In this article, the catalytic mechanism of the E1 subunit has been systematically studied using density functional theory (DFT). Four possible pathways with different general acid/base catalysts in decarboxylation and reductive acylation processes were explored. Our calculation results indicate that the 4′-amino pyrimidine of ThDP and residue His128 are the most likely proton donors in the decarboxylation and reductive acylation processes, respectively. During the reaction, each C-C and C-S bond formation or cleavage process, except for the liberation of CO2, is always accompanied by a proton transfer between the substrates and proton donors. The liberation of CO2 is calculated to be the rate-limiting step for the overall reaction, with an energy barrier of 13.57 kcal/mol. The decarboxylation process is endothermic by 5.32 kcal/mol, whereas the reductive acylation process is exothermic with a value of 5.74 kcal/mol. The assignment of protonation states of the surrounding residues can greatly influence the reaction. Residues His128 and His271 play roles in positioning the first substrate pyruvate and second substrate lipoyl group, respectively. © 2013 American Chemical Society. Source


Wang Z.,Zhengzhou University | Zhang Y.,CAS Northwest Institute of Plateau Biology
Gene | Year: 2012

Erythropoietin (EPO) is a glycoprotein hormone, expressed mainly in fetus liver and adult kidneys. EPO plays an important role in enhancing red blood cell formation in bone marrow under hypoxia. Plateau zokor (. Myospalax baileyi), an subterranean burrowing endemic rodent inhabiting areas of 2 800-4 200. m above sea level on Qinghai-Tibet Plateau, is a typical high hypoxia tolerant mammal with high ratio of oxygen utilization in adaptation to the harsh plateau environment. To investigate the possible mechanisms of adaptation of plateau zokor EPO to high altitude, the complete cDNA and amino acid sequences of plateau zokor EPO have been described. Phylogenetic tree of Epo showed the convergence of the . Spalax and . Myospalax, indicating that, the convergent evolution was driven by similar hypoxic ecological niches. Our results showed that some common sites under positive selection in zokor (116M and 144A) and . Spalax (102R, 116M, 144A and 152P) are the important sites for Epo biological activity. This study thus reports a gene level observation which may be involved in adaptation to underground life at high altitude. © 2012 Elsevier B.V. Source


Wei W.,Qufu Normal University | Liu C.,Qufu Normal University | Yang D.,Qufu Normal University | Wen J.,Qufu Normal University | And 4 more authors.
Chemical Communications | Year: 2013

The first copper-catalyzed oxysulfonylation reaction of alkenes with dioxygen and sulfonylhydrazides for the construction of β-ketosulfones has been developed under mild conditions without any ligand or additive. © 2013 The Royal Society of Chemistry. Source

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