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1.
Nucleophile (11)C/ (14)C [ k (11)/ k (14)] and secondary alpha-deuterium [( k H/ k D) alpha] kinetic isotope effects (KIEs) were measured for the S N2 reactions between tetrabutylammonium cyanide and ethyl iodide, bromide, chloride, and tosylate in anhydrous DMSO at 20 degrees C to determine whether these isotope effects can be used to determine the structure of S N2 transition states. Interpreting the experimental KIEs in the usual fashion (i.e., that a smaller nucleophile KIE indicates the Nu-C alpha transition state bond is shorter and a smaller ( k H/ k D) alpha is found when the Nu-LG distance in the transition state is shorter) suggests that the transition state is tighter with a slightly shorter NC-C alpha bond and a much shorter C alpha-LG bond when the substrate has a poorer halogen leaving group. Theoretical calculations at the B3LYP/aug-cc-pVDZ level of theory support this conclusion. The results show that the experimental nucleophile (11)C/ (14)C KIEs can be used to determine transition-state structure in different reactions and that the usual method of interpreting these KIEs is correct. The magnitude of the experimental secondary alpha-deuterium KIE is related to the nucleophile-leaving group distance in the S N2 transition state ( R TS) for reactions with a halogen leaving group. Unfortunately, the calculated and experimental ( k H/ k D) alpha's change oppositely with leaving group ability. However, the calculated ( k H/ k D) alpha's duplicate both the trend in the KIE with leaving group ability and the magnitude of the ( k H/ k D) alpha's for the ethyl halide reactions when different scale factors are used for the high and the low energy vibrations. This suggests it is critical that different scaling factors for the low and high energy vibrations be used if one wishes to duplicate experimental ( k H/ k D) alpha's. Finally, neither the experimental nor the theoretical secondary alpha-deuterium KIEs for the ethyl tosylate reaction fit the trend found for the reactions with a halogen leaving group. This presumably is found because of the bulky (sterically hindered) leaving group in the tosylate reaction. From every prospective, the tosylate reaction is too different from the halogen reactions to be compared.  相似文献   

2.
The secondary alpha- and beta-deuterium, the alpha-carbon, the nucleophile carbon, the nucleophile nitrogen, and the chlorine leaving group kinetic isotope effects for the S(N)2 reaction between cyanide ion and ethyl chloride were determined in the very slightly polar solvent THF at 30 degrees C. A comparison of these KIEs with those reported earlier for the same reaction in the polar solvent DMSO shows that the transition state in THF is only slightly tighter with very slightly shorter NC-C(alpha) and C(alpha)-Cl bonds. This minor change in transition state structure does not account for the different transition structures that were earlier suggested by interpreting the experimental KIEs and the gas-phase calculations, respectively. It therefore seems unlikely that the different transition states suggested by the two methods are due to the lack of appropriate solvent modeling in the theoretical calculations. Previously it was predicted that the transition state of S(N)2 reactions where the nucleophile and the leaving group have the same charge would be unaffected by a change in solvent. The experimental KIEs support this view.  相似文献   

3.
The secondary alpha-deuterium, the secondary beta-deuterium, the chlorine leaving-group, the nucleophile secondary nitrogen, the nucleophile (12)C/(13)C carbon, and the (11)C/(14)C alpha-carbon kinetic isotope effects (KIEs) and activation parameters have been measured for the S(N)2 reaction between tetrabutylammonium cyanide and ethyl chloride in DMSO at 30 degrees C. Then, thirty-nine readily available different theoretical methods, both including and excluding solvent, were used to calculate the structure of the transition state, the activation energy, and the kinetic isotope effects for the reaction. A comparison of the experimental and theoretical results by using semiempirical, ab initio, and density functional theory methods has shown that the density functional methods are most successful in calculating the experimental isotope effects. With two exceptions, including solvent in the calculation does not improve the fit with the experimental KIEs. Finally, none of the transition states and force constants obtained from the theoretical methods was able to predict all six of the KIEs found by experiment. Moreover, none of the calculated transition structures, which are all early and loose, agree with the late (product-like) transition-state structure suggested by interpreting the experimental KIEs.  相似文献   

4.
[reaction: see text] The transition structures and alpha-carbon 12C/13C kinetic isotope effects for 22 S(N)2 reactions between methyl chloride and a wide variety of nucleophiles have been calculated using the B1LYP/aug-cc-pVDZ level of theory. Anionic, neutral, and radical anion nucleophiles were used to give a wide range of S(N)2 transition states so the relationship between the magnitude of the alpha-carbon kinetic isotope effect and transition-state structure could be determined. The results suggest that the alpha-carbon 12C/13C kinetic isotope effects for S(N)2 reactions will be large (near the experimental maximum) and that the curve relating the magnitude of the KIE to the percent transfer of the alpha-carbon from the nucleophile to the leaving group in the transition state has a broad maximum. This means very similar KIEs will be found for early, symmetric, and late transition states and that one cannot use the magnitude of these KIEs to estimate transition-state structure.  相似文献   

5.
The effect of inert salts on the structure of the transition state has been determined by measuring the secondary alpha deuterium and the chlorine leaving group kinetic isotope effects for the S(N)2 reaction between n-butyl chloride and thiophenoxide ion in both methanol and DMSO. The smaller secondary alpha deuterium isotope effects and very slightly larger chlorine isotope effects found in both solvents when the inert salt is present suggests that the S(N)2 transition state is tighter and more product-like, with a shorter S-C(alpha) and very a slightly longer C(alpha)-Cl bond when the added salt is present. The salt effect on the reaction in methanol where the reacting nucleophile is the solvent-separated ion-pair complex is much greater than the salt effect on the reaction in DMSO where the reacting nucleophile is the free ion. This greater change in transition-state structure found when the inert salt is present in methanol is consistent with the solvation rule for S(N)2 reactions. The greater change in the S-C(alpha) bond is predicted by the bond strength hypothesis. A rationale for the changes found in transition-state structure when the inert salt is present is suggested for both the free-ion and the ion-pair reactions.  相似文献   

6.
Cycloreversion of 4-methoxystyrene from the corresponding Tp'Re(O)(diolato) complex (Tp' = hydrido-tris-(3,5-dimethylpyrazolyl)borate) was measured competitively for various isotopomers at 103 degrees C. Primary ((12)C/(13)C) and secondary ((1)H/(2)H) kinetic isotope effects were determined. The primary KIEs were k(12C)/k(13C) = 1.041 +/- 0.005 at the alpha position and 1.013 +/- 0.006 at the beta position. Secondary KIEs were k(H)/k(D) = 1.076 +/- 0.005 at the alpha position and 1.017 +/- 0.005 at the beta position. Computational modeling (B3LYP/LACVP+) located a transition state for concerted cycloreversion of styrene from TpRe(O)(OCH(2)CHPh) exhibiting dramatically different C-O bond lengths. A Hammett study on cycloreversions of substituted styrenes from a series of Tp'Re(O)(diolato) showed dichotomous behavior for electron donors and electron-withdrawing groups as substituents: rho = -0.65 for electron donors, but rho = +1.13 for electron-withdrawing groups. The data are considered in light of various mechanistic proposals. While the extrusion of 4-methoxystyrene is concluded to be a highly asynchronous concerted reaction, the Hammett study reflects a likelihood that multiple reaction mechanisms are involved.  相似文献   

7.
The chlorine leaving group kinetic isotope effects (KIEs) for the S(N)2 reactions between methyl chloride and a wide range of anionic, neutral, and radical anion nucleophiles were calculated in the gas phase and, in several cases, using a continuum solvent model. In contrast to the expected linear dependence of the chlorine KIEs on the C(alpha)-Cl bond order in the transition state, the KIEs fell in a very small range (1.0056-1.0091), even though the C(alpha)-Cl transition state bond orders varied widely from approximately 0.32 to 0.78, a range from reactant-like to very product-like. This renders chlorine KIEs, and possibly other leaving-group KIEs, less useful for studies of reaction mechanisms than commonly assumed. A partial explanation for this unexpected relationship between the C(alpha)-Cl transition state bond order and the magnitude of the chlorine KIE is presented.  相似文献   

8.
Uridine phosphorylase catalyzes the reversible phosphorolysis of uridine and 2'-deoxyuridine to generate uracil and (2-deoxy)ribose 1-phosphate, an important step in the pyrimidine salvage pathway. The coding sequence annotated as a putative nucleoside phosphorylase in the Trypanosoma cruzi genome was overexpressed in Escherichia coli , purified to homogeneity, and shown to be a homodimeric uridine phosphorylase, with similar specificity for uridine and 2'-deoxyuridine and undetectable activity toward thymidine and purine nucleosides. Competitive kinetic isotope effects (KIEs) were measured and corrected for a forward commitment factor using arsenate as the nucleophile. The intrinsic KIEs are: 1'-(14)C = 1.103, 1,3-(15)N(2) = 1.034, 3-(15)N = 1.004, 1-(15)N = 1.030, 1'-(3)H = 1.132, 2'-(2)H = 1.086, and 5'-(3)H(2) = 1.041 for this reaction. Density functional theory was employed to quantitatively interpret the KIEs in terms of transition-state structure and geometry. Matching of experimental KIEs to proposed transition-state structures suggests an almost synchronous, S(N)2-like transition-state model, in which the ribosyl moiety possesses significant bond order to both nucleophile and leaving groups. Natural bond orbital analysis allowed a comparison of the charge distribution pattern between the ground-state and the transition-state models.  相似文献   

9.
Multiple isotope effects have been measured for the acid-catalyzed hydrolysis of methyl formate in 0.5 M HCl at 20 degrees C. The isotope effects in the present investigation include the carbonyl carbon (13k = 1.028 +/- 0.001), the carbonyl oxygen (18k = 0.9945 +/- 0.0009), the nucleophile oxygen (18k = 0.995 +/- 0.001), and the formyl hydrogen ((D)k = 0.81 +/- 0.02). Determination of the carbonyl carbon, carbonyl oxygen, and formyl hydrogen isotope effects was performed via isotopic analysis of residual substrate. However, determination of the oxygen nucleophile isotope effect required analysis of the oxygen atoms of the product (formic acid), which exchange with the solvent (water) under acid conditions. This necessitated measurement of the rate of exchange of these oxygen atoms under the conditions for hydrolysis (k(ex) = 0.0723 min(-1)) and correction of the raw isotope ratios measured during the nucleophile-O isotope effect experiment. These results, along with the previously reported isotope effect for the leaving oxygen (18k = 1.0009) and the ratio of the rate of hydrolysis to that of exchange of the carbonyl oxygen with water (k(h)/k(ex) = 11.3), give a detailed picture of the transition-state structure for the reaction.  相似文献   

10.
Recombinant human thymidine phosphorylase catalyzes the reaction of arsenate with thymidine to form thymine and 2-deoxyribose 1-arsenate, which rapidly decomposes to 2-deoxyribose and inorganic arsenate. The transition-state structure of this reaction was determined using kinetic isotope effect analysis followed by computer modeling. Experimental kinetic isotope effects were determined at physiological pH and 37 degrees C. The extent of forward commitment to catalysis was determined by pulse-chase experiments to be 0.70%. The intrinsic kinetic isotope effects for [1'-(3)H]-, [2'R-(3)H]-, [2'S-(3)H]-, [4'-(3)H]-, [5'-(3)H]-, [1'-(14)C]-, and [1-(15)N]-thymidines were determined to be 0.989 +/- 0.002, 0.974 +/- 0.002, 1.036 +/- 0.002, 1.020 +/- 0.003, 1.061 +/- 0.003, 1.139 +/- 0.005, and 1.022 +/- 0.005, respectively. A computer-generated model, based on density functional electronic structure calculations, was fit to the experimental isotope effect. The structure of the transition state confirms that human thymidine phosphorylase proceeds through an S(N)2-like transition state with bond orders of 0.50 to the thymine leaving group and 0.33 to the attacking oxygen nucleophile. The reaction differs from the dissociative transition states previously reported for N-ribosyl transferases and is the first demonstration of a nucleophilic transition state for an N-ribosyl transferase. The large primary (14)C isotope effect of 1.139 can occur only in nucleophilic displacements and is the largest (14)C primary isotope effect reported for an enzymatic reaction. A transition state structure with substantial bond order to the attacking nucleophile and leaving group is confirmed by the slightly inverse 1'-(3)H isotope effect, demonstrating that the transition state is compressed by the impinging steric bulk of the nucleophile and leaving group.  相似文献   

11.
Kinetic isotope effects (KIEs) and computer modeling using density functional theory were used to approximate the transition state of human 5'-methylthioadenosine phosphorylase (MTAP). KIEs were measured on the arsenolysis of 5'-methylthioadenosine (MTA) catalyzed by MTAP and were corrected for the forward commitment to catalysis. Intrinsic KIEs were obtained for [1'-(3)H], [1'-(14)C], [2'-(3)H], [4'-(3)H], [5'-(3)H(2)], [9-(15)N], and [Me-(3)H(3)] MTAs. The primary intrinsic KIEs (1'-(14)C and 9-(15)N) suggest that MTAP has a dissociative S(N)1 transition state with its cationic center at the anomeric carbon and insignificant bond order to the leaving group. The 9-(15)N intrinsic KIE of 1.039 also establishes an anionic character for the adenine leaving group, whereas the alpha-primary 1'-(14)C KIE of 1.031 indicates significant nucleophilic participation at the transition state. Computational matching of the calculated EIEs to the intrinsic isotope effects places the oxygen nucleophile 2.0 Angstrom from the anomeric carbon. The 4'-(3)H KIE is sensitive to the polarization of the 3'-OH group. Calculations suggest that a 4'-(3)H KIE of 1.047 is consistent with ionization of the 3'-OH group, indicating formation of a zwitterion at the transition state. The transition state has cationic character at the anomeric carbon and is anionic at the 3'-OH oxygen, with an anionic leaving group. The isotope effects predicted a 3'-endo conformation for the ribosyl zwitterion, corresponding to a H1'-C1'-C2'-H2' torsional angle of 33 degrees. The [Me-(3)H(3)] and [5'-(3)H(2)] KIEs arise predominantly from the negative hyperconjugation of the lone pairs of sulfur with the sigma (C-H) antibonding orbitals. Human MTAP is characterized by a late S(N)1 transition state with significant participation of the phosphate nucleophile.  相似文献   

12.
The C2-C6 (Schmittel)/ene cyclization of enyne-allenes is studied by a combination of kinetic isotope effects, theoretical calculations, and dynamics trajectories. For the cyclization of allenol acetate 9, the isotope effect (k(CH3)/k(CD3) is approximately 1.43. The isotope effect is interpreted in terms of a highly asynchronous transition state near the concerted/stepwise boundary. This is supported by density functional theory calculations that locate a highly asynchronous transition structure for the concerted ene reaction. However, calculations of both the experimental system and a model reaction were unable to locate a transition structure for formation of the diradical intermediate of a stepwise mechanism. The stepwise mechanism and the asynchronous concerted mechanism start out geometrically similar, and the two pathways appear to have merged as far as the initial transition structure. For the model reaction, quasiclassical direct dynamics trajectories emanating from the initial transition structure afforded the diradical intermediate in 29 out of 101 trajectories. A large portion of the remaining trajectories completes hydrogen transfer before carbon-carbon bond formation, despite the advanced carbon-carbon bond formation in the asynchronous transition structure. Overall, the single minimum-energy path from starting material to product is inadequate to describe the reaction, and a consideration of dynamic effects is necessary to understand the mechanism. The implications of these observations toward questions of concert in other reactions are discussed.  相似文献   

13.
The epoxidation of beta-methylstyrene catalyzed by the Shi fructose-derived ketone is studied using experimental kinetic isotope effects and DFT calculations. The observation of a large beta olefinic (13)C isotope effect and small alpha carbon isotope effect is indicative of an asynchronous transition state with more advanced formation of the C-O bond to the beta olefinic carbon. By varying the catalyst conformation and alkene orientation, diverse transition structure geometries were located calculationally, and the lowest-energy structure leads to an accurate prediction of the isotope effects. Given this support for the accuracy of the calculations employed, the nature of enantioselectivity in this and related epoxidations is considered. The lowest-energy transition structures are generally those in which the differential formation of the incipient C-O bonds, the "asynchronicity," resembles that of an unhindered model, and the imposition of greater or less asynchronicity leads to higher barriers. In reactions of cis-disubstituted and terminal alkenes using Shi's oxazolidinone catalyst, the asynchronicity of the epoxidation transition state leads to increased steric interaction with the oxazolidinone when a pi-conjugating substituent is distal to the oxazolidinone but decreased steric interaction when the pi-conjugating substituent is proximal to the oxazolidinone. Overall, the asynchronicity of the transition state must be considered carefully to understand the enantioselectivity.  相似文献   

14.
The addition reaction of benzylamine (XC6H4CH2NH2) to benzylidene-3,5-heptadione (BHD; YC6H(4-)CH=C(COEt)(2)) in acetonitrile is investigated. The rate is slower than the corresponding rate for benzylidenediethylmalonate (YC6H4CH=C(OOEt)(2)) as the result of a greater steric hindrance in the planar dicarbonyl transition state. The kinetic isotope effects (k(H)/k(D)) involving deuterated amine nucleophiles (XC6H4CH2ND2) are greater than 1 (1.37-2.04), indicating N-H bond stretching with concurrent N-C(alpha) and H-C(beta) bond formation in the TS. The trend of change in k(H)/k(D) with variation of substituent X in the nucleophile conforms to the Bell-Evans-Polanyi principle. It has been stressed that the dicarbonyl group activated olefins exhibit insignificant charge imbalance in the TS for the benzylamine additions in acetonitrile as a result of the two strong n(c) --> pi*(C=O) vicinal charge-transfer interactions.  相似文献   

15.
Carbon-13 kinetic isotope effects (KIEs) have been determined for free-radical and copper-mediated living radical polymerizations of methyl methacrylate at 60 degrees C. While free-radical polymerization shows only one primary 13C KIE, on the least-substituted double bond carbon (k12/k13 = 1.045), two significant KIEs are observed, one on each double bond carbon, for copper-mediated polymerization (k12/k13(H2C=) = 1.050, k12/k13(=C <) = 1.010), showing that copper-mediated living radical polymerization does not propagate via a simple free radical process.  相似文献   

16.
The mechanism of the epoxidation of 2-cyclohexen-1-one with tert-butyl hydroperoxide mediated by DBU was studied by a combination of experimental kinetic isotope effects (KIEs) and theoretical calculations. A large 12C/13C (k(12C)/k(13C)) isotope effect of approximately equal to 1.032 was observed at the C3 (beta) position of cyclohexenone, while a much smaller 12C/13C isotope effect of 1.010 was observed at the C2 (alpha) position. Qualitatively, these results are indicative of nucleophilic addition to the enone being the rate-limiting step. Theoretical calculations support this interpretation. Transition structures for the addition step lead to predicted isotope effects that approximate the experimental values, while the predicted isotope effects for the ring-closure step are not consistent with the experimental values. The calculations correctly favor a rate-limiting addition step but suggest that the barriers for the addition and ring-closure steps are crudely similar in energy. The stereochemistry of these epoxidations is predicted to be governed by a preference for an initial axial addition, and the role of this preference in experimental diastereoselectivity observations is discussed.  相似文献   

17.
The gas-phase reactions of F(-)(CH(3)OH) and F(-)(C(2)H(5)OH) with t-butyl bromide have been investigated to explore the effect of the solvent on the E2 transition state. Kinetic isotope effects (KIEs) were measured using a flowing afterglow-selected ion flow tube (FA-SIFT) mass spectrometer upon deuteration of both the alkyl halide and the alcohol. Kinetic isotope effects are significantly more pronounced than those previously observed for similar reactions of F(-)(H(2)O) with t-butyl halides. KIEs for the reaction of F(-)(CH(3)OH) with t-butyl bromide are 2.10 upon deuteration of the neutral reagent and 0.74 upon deuteration of the solvent. KIEs for the reaction of F(-)(C(2)H(5)OH) with t-butyl bromide are 3.84 upon deuteration of the neutral reagent and 0.66 upon deuteration of the solvent. The magnitude of these effects is discussed in terms of transition-state looseness. Additionally, deuteration of the neutral regent and deuteration of the solvent do not produce completely separable isotope effects, which is likely due to a crowded transition state. These results are compared to our previous work on S(N)2 and E2 solvated systems.  相似文献   

18.
Phosphoryl transfer reactions are ubiquitous in biology and the understanding of the mechanisms whereby these reactions are catalyzed by protein and RNA enzymes is central to reveal design principles for new therapeutics. Two of the most powerful experimental probes of chemical mechanism involve the analysis of linear free energy relations (LFERs) and the measurement of kinetic isotope effects (KIEs). These experimental data report directly on differences in bonding between the ground state and the rate‐controlling transition state, which is the most critical point along the reaction free energy pathway. However, interpretation of LFER and KIE data in terms of transition‐state structure and bonding optimally requires the use of theoretical models. In this work, we apply density‐functional calculations to determine KIEs for a series of phosphoryl transfer reactions of direct relevance to the 2′‐O‐transphosphorylation that leads to cleavage of the phosphodiester backbone of RNA. We first examine a well‐studied series of phosphate and phosphorothioate mono‐, di‐ and triesters that are useful as mechanistic probes and for which KIEs have been measured. Close agreement is demonstrated between the calculated and measured KIEs, establishing the reliability of our quantum model calculations. Next, we examine a series of RNA transesterification model reactions with a wide range of leaving groups in order to provide a direct connection between observed Brønsted coefficients and KIEs with the structure and bonding in the transition state. These relations can be used for prediction or to aid in the interpretation of experimental data for similar non‐enzymatic and enzymatic reactions. Finally, we apply these relations to RNA phosphoryl transfer catalyzed by ribonuclease A, and demonstrate the reaction coordinate–KIE correlation is reasonably preserved. A prediction of the secondary deuterium KIE in this reaction is also provided. These results demonstrate the utility of building up knowledge of mechanism through the systematic study of model systems to provide insight into more complex biological systems such as phosphoryl transfer enzymes and ribozymes.  相似文献   

19.
Elimination reactions of 2-X-4-NO2C6H3CH2C(O)OC6H3-2-Y-4-NO2 [X = H (1), NO2 (2)] promoted by R2NH/R2NH2+ in 70 mol % MeCN(aq) have been studied kinetically. The base-promoted eliminations from 1 proceeded by the E2 mechanism when Y = Cl, CF3, and NO2. The mechanism changed to the competing E2 and E1cb mechanisms by the poorer leaving groups (Y = H, OMe) and to the E1cb extreme by the strongly electron-withdrawing beta-aryl group (2, X = NO2). The values of beta = 0.14 and beta(lg) = 0.10-0.21 calculated for elimination from 1 (Y = NO2) indicate a reactant-like transition state with small extents of proton transfer and C(alpha)-OAr bond cleavage. The extent of proton transfer increased with a poorer leaving group, and the degree of leaving group bond cleavage increased with a weaker base. Also, the changes in the k(1) and k(-1)/k(2) values with the reactant structure variation are consistent with the E1cb mechanism. From these results, a plausible pathway of the change of the mechanism from E2 to the E1cb extreme is proposed.  相似文献   

20.
In recent years, the temperature dependence of primary kinetic isotope effects (KIE) has been used as indicator for the physical nature of enzyme-catalyzed H-transfer reactions. An interactive study where experimental data and calculations examine the same chemical transformation is a critical means to interpret more properly temperature dependence of KIEs. Here, the rate-limiting step of the thymidylate synthase-catalyzed reaction has been studied by means of hybrid quantum mechanics/molecular mechanics (QM/MM) simulations in the theoretical framework of the ensemble-averaged variational transition-state theory with multidimensional tunneling (EA-VTST/MT) combined with Grote-Hynes theory. The KIEs were calculated across the same temperature range examined experimentally, revealing a temperature independent behavior, in agreement with experimental findings. The calculations show that the H-transfer proceeds with ~91% by tunneling in the case of protium and ~80% when the transferred protium is replaced by tritium. Dynamic recrossing coefficients are almost invariant with temperature and in all cases far from unity, showing significant coupling between protein motions and the reaction coordinate. In particular, the relative movement of a conserved arginine (Arg166 in Escherichia coli ) promotes the departure of a conserved cysteine (Cys146 in E. coli ) from the dUMP by polarizing the thioether bond thus facilitating this bond breaking that takes place concomitantly with the hydride transfer. These promoting vibrations of the enzyme, which represent some of the dimensions of the real reaction coordinate, would limit the search through configurational space to efficiently find those decreasing both barrier height and width, thereby enhancing the probability of H-transfer by either tunneling (through barrier) or classical (over-the-barrier) mechanisms. In other words, the thermal fluctuations that are coupled to the reaction coordinate, together with transition-state geometries and tunneling, are the same in different bath temperatures (within the limited experimental range examined). All these terms contribute to the observed temperature independent KIEs in thymidylate synthase.  相似文献   

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