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Tong C.,CAS Northwest Institute of Plateau Biology | Tong C.,University of Chinese Academy of Sciences | Fei T.,CAS Northwest Institute of Plateau Biology | Zhang C.,CAS Northwest Institute of Plateau Biology | Zhao K.,CAS Northwest Institute of Plateau Biology
BMC Evolutionary Biology | Year: 2017

Background: Understanding the genetic basis of adaptation to high altitude life is of paramount importance for preserving and managing genetic diversity in highland animals. This objective has been addressed mainly in terrestrial fauna but rarely in aquatic animals. Tibetan Schizothoracinae fish is the ideal model system in evolutionary biology, carrying key insights into evolutionary genetics of speciation and adaptation at high altitude. Gymnocypris przewalskii is the newly formed Schizothoracinae fish species in the Tibetan Plateau, inhabits chronic cold, extreme saline and alkaline aquatic environment in Lake Qinghai, thus evolving the unique genomic signatures to adapt extremely severe environments. Results: To characterize its genomic features, we assembled de novo transcriptome of G. przewalskii from Lake Qinghai. Intriguingly, by comparative genomic analyses of G. przewalskii and 8 other fish species, we identified potential expansions in gene families related to energy metabolism, transport and developmental functions, possibly underlying the adaptation to these environmental stresses. Through comprehensive molecular evolution analyses, we found that sets of genes controlling mitochondrion, ion homoeostasis, acid-base balance and innate immunity show significant signals of positive selection. Compared to previous studies on highland fishes, we failed to identify any positively selected genes related to hypoxia response. Conclusions: Our findings provide comprehensive insights into the genetic basis of teleost fish that underlie their adaptation to extreme high altitude aquatic life on the Tibetan Plateau. © 2017 The Author(s).


Wang Y.-C.,CAS Northwest Institute of Plateau Biology | Chen S.-L.,CAS Northwest Institute of Plateau Biology | Deng N.-Y.,China Agricultural University | Wang Y.,Chinese Academy of Sciences | Wang Y.,CAS Academy of Mathematics and Systems Science
Bioinformatics | Year: 2013

Motivation: Discovering drug's Anatomical Therapeutic Chemical (ATC) classification rules at molecular level is of vital importance to understand a vast majority of drugs action. However, few studies attempt to annotate drug's potential ATC-codes by computational approaches.Results: Here, we introduce drug-target network to computationally predict drug's ATC-codes and propose a novel method named NetPredATC. Starting from the assumption that drugs with similar chemical structures or target proteins share common ATC-codes, our method, NetPredATC, aims to assign drug's potential ATC-codes by integrating chemical structures and target proteins. Specifically, we first construct a gold-standard positive dataset from drugs' ATC-code annotation databases. Then we characterize ATC-code and drug by their similarity profiles and define kernel function to correlate them. Finally, we use a kernel method, support vector machine, to automatically predict drug's ATC-codes. Our method was validated on four drug datasets with various target proteins, including enzymes, ion channels, G-protein couple receptors and nuclear receptors. We found that both drug's chemical structure and target protein are predictive, and target protein information has better accuracy. Further integrating these two data sources revealed more experimentally validated ATC-codes for drugs. We extensively compared our NetPredATC with SuperPred, which is a chemical similarity-only based method. Experimental results showed that our NetPredATC outperforms SuperPred not only in predictive coverage but also in accuracy. In addition, database search and functional annotation analysis support that our novel predictions are worthy of future experimental validation.Conclusion: In conclusion, our new method, NetPredATC, can predict drug's ATC-codes more accurately by incorporating drug-target network and integrating data, which will promote drug mechanism understanding and drug repositioning and discovery. © 2013 The Author. Published by Oxford University Press. All rights reserved.


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.


Sheng X.,Shandong University | Liu Y.,Shandong University | Liu Y.,CAS Northwest Institute of Plateau Biology
Biochemistry | Year: 2014

Pyruvate carboxylase (PC) catalyzes the carboxylation of pyruvate to produce oxaloacetate. Its activity is directly related to insulin release and thus PC has recently attracted great interest as a potential target for diabetes treatment. In this article, the catalytic mechanism of the carboxyl transferase domain of PC from Staphylococcus aureus was investigated by using a combined quantum-mechanical/molecular-mechanical approach. Our calculation results indicate that the catalytic reaction starts from the decarboxylation of carboxybiotin to generate an enol-BTI intermediate, followed by two consecutive proton-transfer processes (from T908 to enol-BTI and from PYR to T908). During the catalytic reaction, the main-chain amide of T908 plays a key role in catching CO2 and preventing its diffusion from the active center. A triad of residues, R571, Q575, and K741, contributes both to substrate binding and enol-pyruvate stabilization. The oxyanion hole, consisting of the side-chain hydroxyl of S911 and the side-chain amino of Q870, plays an important role in stabilizing the hydroxyl anion of BTI. The coordination of the metal cation by pyruvate is a second sphere, rather than an inner sphere, interaction, and the metal cation stabilizes the species through the medium of residue K741. The decarboxylation of carboxybiotin corresponds to the highest free energy barrier of 21.7 kcal/mol. Our results may provide useful information for both the regulation of enzyme activity and the development of related biocatalytic applications. © 2014 American Chemical Society.


Wang Q.L.,CAS Northwest Institute of Plateau Biology
Ying yong sheng tai xue bao = The journal of applied ecology / Zhongguo sheng tai xue xue hui, Zhongguo ke xue yuan Shenyang ying yong sheng tai yan jiu suo zhu ban | Year: 2011

Taking the typical alpine meadows Potentilla froticosa shrub meadow, Kobresia humilis meadow, and K. pygmaea meadow in the Haibei State of Qinghai Province as the research objects, a comprehensive assessment of soil quality was conducted by principal component analysis (PCA), with seven indices of soil microbial activities and ten indices of soil chemical properties. The soil quality of the alpine meadow could be characterized by three principal components (PC). In the first component (PC1), 13 indices had high factorial loads; in the second component (PC2), 3 indices had high factorial loads; in the third component (PC3), only one index, total phosphors, had high factorial load. In combining with Norm values, eleven indices including microbial biomass carbon (MBC), urease, alkaline phosphatase, protease, organic matter, total N, available N, available P, available K, bulk density, and CEC were selected to establish minimum data set (MDS) for the comprehensive assessment of soil quality of alpine meadow in Haibei. The PCA and corresponding weight coefficient analysis showed that the soil quality (0-10 cm and 10-20 cm layers) of the three kind meadows was in the order of K. humilis meadow > P. froticosa shrub meadow > K. pygmaea meadow, and P. froticosa shrub meadow > K. pygmaea meadow > K. humilis meadow, respectively.


Wang H.,Simon Fraser University | Wang H.,CAS Northwest Institute of Plateau Biology | Ou L.M.L.,Simon Fraser University | Suo Y.,CAS Northwest Institute of Plateau Biology | Yu H.-Z.,Simon Fraser University
Analytical Chemistry | Year: 2011

A method for the convenient detection of lead at the parts-per-billion (ppb)-level has been developed; it uses a conventional compact disc (CD) as the platform for preparing DNAzyme assays and an unmodified optical drive of ordinary desktop/laptop computers as the readout device. In particular, by immobilization of Pb2+-specific DNAzyme sensing constructs on the transparent side of a conventional CD-R via mild surface reactions, the Pb 2+ concentration can be determined by a free diagnostic program that checks the error distribution on the CD (i.e., it extracts the number of errors in a prerecorded audio file). The reading errors increase monotonically over a wide range of Pb2+ concentrations (from 10 nM to 1 mM), and the selectivity is confirmed by testing several other divalent cations (Zn 2+, Ba2+, Mg2+, Ca2+, Cu 2+, and Hg2+). © 2011 American Chemical Society.


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.


Zhang R.Y.,CAS Northwest Institute of Plateau Biology
Dong wu xue yan jiu = Zoological research / "Dong wu xue yan jiu" bian ji wei yuan hui bian ji | Year: 2013

Gill morphologies of two subspecies of Gymnocypris przewalskii (Gymnocypris przewalskii przewalskii and Gymnocypris przewalskii ganzihonensis) in different habitats were analyzed under scanning electron microscope. Results indicated that G. p. przewalskii had numerous long and dense-lined gill rakers while G. p. ganzihonensis had few short and scatter-lined gill rakers. There were no significant differences in distance between gill filaments (DBF) and distance gill lamella (DBL) between the two subspecies, but gill filaments of G. p. przewalskii were longer than in G. p. ganzihonensis. The electron microscopic study indicated that the pavement epithelium cells of G. p. przewalskii were well defined as irregular ovals, but were hexagonal in G. p. ganzihonensis. Moreover, G. p. przewalskii had more chloride cells than G. p. ganzihonensis, and mucous cells were only found on the surface of gill filaments of G. p. przewalskii. The morphological differences between the two subspecies of G. przewalskii are adaptations to their corresponding diets and habitats.


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.


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.

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