Computer simulation and analysis of the reaction pathway of triosephosphate isomerase

Bash, Paul A.; Field, Martin J.; Davenport, Robert C.; Petsko, Gregory A.; Ringe, Dagmar; Karplus, Martin

doi:10.1021/bi00238a003

Cited by 286 publications

(301 citation statements)

References 42 publications

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“…Figure 7 here In general, our study supports the notion that Coulomb interactions play a major role in governing chemical transformations in a protein [82,87,88,89,90]. However, Coulomb interactions cannot be properly accounted for by mere pairwise potentials of classical electrostatics, since the protein charge environment polarizes significantly the substrate and alters its electronic structure.…”

Section: Effective Energy Barrier Of Dark Adaptationsupporting

confidence: 79%

“…Later, various techniques were developed which allow for the self-consistent ab initio treatment of a molecule embedded in a dielectric continuum [75,76,77]. At present, there exist a number of ab initio as well as semi-empirical techniques which try to account for the realistic atomic structure and charge distribution of the environment via explicit incorporation of protein (or solution) point charges in the electronic Hamiltonian of the quantum chemically treated substrate [78,79,80,81,82,83].…”

Section: Quantum Chemistry Of In Situ Retinalmentioning

confidence: 99%

“…It has been observed that modification of protein groups in the vicinity of the retinal Schiff base shifts considerably the bR absorption spectrum [69] and affects drastically the rates of both thermally- [70] and photo- [71,72] [75,76,77]. At present, there exist a number of ab initio as well as semi-empirical techniques which try to account for the realistic atomic structure and charge distribution of the environment via explicit incorporation of protein (or solution) point charges in the electronic Hamiltonian of the quantum chemically treated substrate [78,79,80,81,82,83].In our study, the refined structure of bacteriorhodopsin reported in [31] was used as a starting point for all the computations. This structure, corresponding to the bR 568 pigment, is depicted in Figures 2a and 5b.…”

mentioning

confidence: 99%

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Quantum Chemistry of in situ Retinal: Study of the Spectral Properties and Dark Adaptation of Bacteriorhodopsin

Logunov

Schulten

1996

Quantum Mechanical Simulation Methods for Studying Biological Systems

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1A combination of molecular dynamics and quantum chemistry techniques have been employed to study the electronic excitation and conformational potential surface of retinal in the binding site of bacteriorhodopsin (bR). The CASSCF(6,9)/6-31G level of ab initio calculations (within Gaussian92) has been used for the treatment of both the ground (S0) and excited (S1) states of retinal. Charges of all atoms in the protein are represented by spherical Gaussians and explicitly included in the electronic Hamiltonian of retinal. Spectral properties have been analyzed for the native bR pigment as well as for its D85N mutant.The calculated relative shift in the absorption maxima between the two pigments is in better agreement with experiment than the computed absolute parameters of the absorption line shapes. The dark adaptation processes in bacteriorhodopsin (which involves rotation around the 13-14 and the 15-N retinal double bonds) has been modelled by following the pre-defined reaction coordinate. Our simulations support the notion that the isomerization process is catalyzed by the protonation of an aspartic acid (Asp85) side group of bacteriorhodopsin. 2 IntroductionBacteriorhodopsin (bR) spans the cell membrane of Halobacterium halobium and functions as a light-driven proton pump. bR contains seven α-helices which enclose the prosthetic group, all-trans retinal, bound via a protonated Schiff base linkage to Lys-216. Figure 1a shows the chemical structure of retinal and its conventional numbering scheme. The bR structure is presented in Fig. 2a. Retinal absorbs light and undergoes a photoisomerization process; the thermal reversal of this reaction is coupled to transfer of a proton from the cytoplasmic side (top in Fig. 2a) to the extracellular side (bottom in Fig. 2a) of the protein.Recent reviews that discuss the structure and function of bR are [1,2,3,4,5,6,7]. Figure 1 here Bacteriorhodopsin accomplishes its function through a cyclic process initiated by absorption of a photon. This photon triggers an isomerization of retinal, which proceeds then through several intermediate states identified by their absorption spectra. An accepted kinetic scheme for this cycle is an unbranched series of intermediates, shown in Fig. 3. Photoisomerization occurs in the bR 568 → J 625 transition. During the L 550 → M 412 transition the Schiff base proton is transferred to Asp-85 and, subsequently, to the outside of the cell [8,9,10,11,12,13]. During the M 412 → N 520 transition, a proton is transferred to the Schiff base from Asp-96, which then takes up a proton from the cytoplasmic environment [13]. The reaction cycle is completed as the protein returns to bR 568 via the O 640 intermediate. Figure 2 here When bR is allowed to equilibrate in the dark, it converts within an hour to a 2:1 mixture containing 13-cis retinal and all-trans retinal bR [14]. The protein containing the 13-cis retinal isomer of bRis referred to as the dark adapted (DA) pigment of bR, bR 548 , which absorbs at 548 nm. bR 548 contains, actually, retinal in a 1...

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Section: Effective Energy Barrier Of Dark Adaptationsupporting

confidence: 79%

Section: Quantum Chemistry Of In Situ Retinalmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Quantum Chemistry of in situ Retinal: Study of the Spectral Properties and Dark Adaptation of Bacteriorhodopsin

Logunov

Schulten

1996

Quantum Mechanical Simulation Methods for Studying Biological Systems

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“…1a). Despite numerous experimental (4 -9) and theoretical studies (10,11), the precise mechanism of the multi-step reaction catalyzed by TIM is still under active discussion.…”

Section: Triose-phosphate Isomerase (Tim)mentioning

confidence: 99%

Structure of Plasmodium falciparum Triose-phosphate Isomerase-2-Phosphoglycerate Complex at 1.1-Å Resolution

Parthasarathy

Kandiah

Balaram

et al. 2003

Journal of Biological Chemistry

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Triose-phosphate isomerase, a key enzyme of the glycolytic pathway, catalyzes the isomerization of dihydroxy acetone phosphate and glyceraldehyde 3-phosphate. In this communication we report the crystal structure of Plasmodium falciparum triose-phosphate isomerase complexed to the inhibitor 2-phosphoglycerate at 1.1-Å resolution. The crystallographic asymmetric unit contains a dimeric molecule. The inhibitor bound to one of the subunits in which the flexible catalytic loop 6 is in the open conformation has been cleaved into two fragments presumably due to radiation damage. The cleavage products have been tentatively identified as 2-oxoglycerate and meta-phosphate. The intact 2-phosphoglycerate bound to the active site of the other subunit has been observed in two different orientations. The active site loop in this subunit is in both open and "closed" conformations, although the open form is predominant. Concomitant with the loop closure, Phe-96, Leu-167, and residues 208 -211 (YGGS) are also observed in dual conformations in the B-subunit. Detailed comparison of the active-site geometry in the present case to the Saccharomyces cerevisiae triose-phosphate isomerase-dihydroxy acetone phosphate and Leishmania mexicana triose-phosphate isomerase-phosphoglycolate complexes, which have also been determined at atomic resolution, shows that certain interactions are common to the three structures, although 2-phosphoglycerate is neither a substrate nor a transition state analogue. Triose-phosphate isomerase (TIM)1 is a ubiquitous glycolytic enzyme that catalyzes the isomerization of dihydroxy acetone phosphate (DHAP) and glyceraldehyde 3-phosphate through the intermediate formation of cis-enediol(ate(s)). Commenting on the catalytic efficiency of TIM, Knowles (1) states "This enzyme (TIM) appears to have arrived at the end of its evolutionary development as a catalyst." It has been argued that the evolutionary pressure for TIM to be a perfect catalyst has been intense, since for "flight or fight" there is an instant requirement for muscle ATP. The catalytic reaction of TIM is chemically simple and involves intermolecular protonation and deprotonation between the enzyme and substrate. The enzyme achieves the proton transfers with the help of certain elements as catalytic tools, a 10-residue loop that closes over the active site and stabilizes the reaction intermediate and a catalytic base and an acid to perform the enolization steps (1). It is believed that catalysis is a result of stronger binding of the enzyme to its transition state than to the initial enzyme-substrate complex (2). Although various schemes for this reaction have been proposed (for a review of the schemes, see Cui and Karplus (3)), the most frequently discussed mechanism is the one that involves Glu-165 as the catalytic base in the first proton transfer and His-95 as the catalytic acid for the rest of the reaction (3) (Fig. 1a). Despite numerous experimental (4 -9) and theoretical studies (10, 11), the precise mechanism of the multi-step reaction cataly...

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“…In TIM, His-95 was proposed to act as an electrophile to polarize the carbonyl group in the catalysis of the enolization reaction of the substrate dihydroxyacetone phosphate. In addition, His-95 was postulated to stabilize the cis-enediol(ate) intermediate(s) by mediating proton transfer between the oxygen atoms on C1 and C2 (59), through a possible imidazole͞imidazolate pair acting as an acid͞base catalyst (60). Intramolecular proton transfer between O1 and O2 of the two enediolate intermediates has also been proposed as a possible alternative (61), however reported as less energetically favorable according to some other theoretical studies (62,63).…”

Section: Comparison Of Pgi͞5pah To Complexes Of Tim and Xyl With Analmentioning

confidence: 99%

The crystal structure of rabbit phosphoglucose isomerase complexed with 5-phospho- d -arabinonohydroxamic acid

Arsenieva

Hardré

Salmon

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Phosphoglucose isomerase (EC 5.3.1.9) catalyzes the second step in glycolysis, the reversible isomerization of D-glucose 6-phosphate to D-fructose 6-phosphate. The reaction mechanism involves acid-base catalysis with proton transfer and proceeds through a cis-enediol(ate) intermediate. 5-Phospho-D-arabinonohydroxamic acid (5PAH) is a synthetic small molecule that resembles the reaction intermediate, differing only in that it has a nitrogen atom in place of C1. Hence, 5PAH is the best inhibitor of the isomerization reaction reported to date with a Ki of 2 ؋ 10 ؊7 M. Here we report the crystal structure of rabbit phosphoglucose isomerase complexed with 5PAH at 1.9 Å resolution. The interaction of 5PAH with amino acid residues in the enzyme active site supports a model of the catalytic mechanism in which Glu-357 transfers a proton between C1 and C2 and Arg-272 helps stabilize the intermediate. It also suggests a mechanism for proton transfer between O1 and O2. P hosphoglucose isomerase (PGI; EC 5.3.1.9) is a cytosolic glycolytic enzyme that catalyzes the reversible isomerization of D-glucose 6-phosphate (G6P) to D-fructose 6-phosphate (F6P). In addition to isomerase activity, PGI has been shown to display anomerase activity between pyranose anomers of G6P (1), between furanose anomers of F6P (2), and between those of D-mannose 6-phosphate (3), as well as C-2-epimerase activity on G6P (4). It also has roles in protein glycosylation, gluconeogenesis, and the pentose phosphate pathway (5). This central role in the metabolism of phosphorylated sugars explains the strong impact of PGI deficiency in humans (6, 7), as well as the interest as a therapeutic target in parasite metabolism (8). The PGI polypeptide chain, or perhaps a variation thereof, also has extracellular roles as neuroleukin, autocrine motility factor, and differentiation and maturation mediator (9-12). These proteins promote antibody secretion by mononuclear cells, tumor cell motility, and differentiation of leukemia cells and a promyelocytic cell line (HL-60 cells), respectively. More recently, PGI has also been identified as the antigen involved in rheumatoid arthritis of a mouse line (13), as a specific inhibitor toward myofibril-bound serine proteinase (14), and as the surface antigen involved in sperm agglutination (15). Because very little is known about how PGI is precisely involved in these various biological processes, this moonlighting protein (16) has been the subject of intense investigations.Biochemical characterization of PGI began over 50 years ago and includes inhibitor studies (1,(17)(18)(19)(20)(21)(22)(23)(24)(25), labeling studies (26-32), solvent exchange (33, 34), mutagenesis (35,36), and pH profile studies (20,37). A proposed multistep catalytic mechanism includes a ring-opening step followed by an isomerization step. The isomerization step proceeds via general acid-base catalysis with proton transfer. In the G6P to F6P direction, abstraction of the proton from C2 by an active site amino acid residue yields a 1,2-cis-enediol(ate) in...

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Computer simulation and analysis of the reaction pathway of triosephosphate isomerase

Cited by 286 publications

References 42 publications

Quantum Chemistry of in situ Retinal: Study of the Spectral Properties and Dark Adaptation of Bacteriorhodopsin

Quantum Chemistry of in situ Retinal: Study of the Spectral Properties and Dark Adaptation of Bacteriorhodopsin

Structure of Plasmodium falciparum Triose-phosphate Isomerase-2-Phosphoglycerate Complex at 1.1-Å Resolution

The crystal structure of rabbit phosphoglucose isomerase complexed with 5-phospho- d -arabinonohydroxamic acid

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