Structural Rationale for the Affinity of Pico- and Femtomolar Transition State Analogues of Escherichia coli 5′-Methylthioadenosine/S-Adenosylhomocysteine Nucleosidase

Immucillin and DADMe-Immucillin inhibitors are tight binding transition state mimics of purine nucleoside phosphorylases (PNP). 5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is proposed to form a similar transition state structure as PNP. The companion paper describes modifications of the Immucillin and DADMe-Immucillin inhibitors to better match transition state features of MTAN and have led to 5′-thio aromatic substitutions that extend the inhibition constants to the femtomolar range (Singh, V., Evans, G. B., Lenz, D. H., Mason, J., Clinch, K., Mee, S., Painter, G. F., Tyler, P. C., Furneaux, R. H., Lee, J. E., Howell, P. L., and Schramm, V. L. (2005) J. Biol. Chem. 280, 18265-18273). 5′-Methylthio-Immucillin A (MT-ImmA) and 5′-methylthio-DADMe-Immucillin A (MT-DADMe-ImmA) exhibit slow-onset inhibition with Ki* of 77 and 2 pm, respectively, and were selected for structural analysis as the parent compounds of each class of transition state analogue. The crystal structures of Escherichia coli MTAN complexed with MT-ImmA and MT-DADMe-ImmA were determined to 2.2 Å resolution and compared with the existing MTAN inhibitor complexes. These MTAN-transition state complexes are among the tightest binding enzyme-ligand complexes ever described and analysis of their mode of binding provides extraordinary insight into the structural basis for their affinity. The MTAN-MT-ImmA complex reveals the presence of a new ion pair between the 4′-iminoribitol atom and the nucleophilic water (WAT3) that captures key features of the transition state. Similarly, in the MTAN-MT-DADMe-ImmA complex a favorable hydrogen bond or ion pair interaction between the cationic 1′-pyrrolidine atom and WAT3 is crucial for tight affinity. Distance analysis of the nucleophile and leaving group show that MT-ImmA is a mimic of an early transition state, while MT-DADMe-ImmA is a better mimic of the highly dissociated transition state of E. coli MTAN. Immucillin and DADMe-Immucillin inhibitors are tight binding transition state mimics of purine nucleoside phosphorylases (PNP). 5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is proposed to form a similar transition state structure as PNP. The companion paper describes modifications of the Immucillin and DADMe-Immucillin inhibitors to better match transition state features of MTAN and have led to 5′-thio aromatic substitutions that extend the inhibition constants to the femtomolar range (Singh, V., Evans, G. B., Lenz, D. H., Mason, J., Clinch, K., Mee, S., Painter, G. F., Tyler, P. C., Furneaux, R. H., Lee, J. E., Howell, P. L., and Schramm, V. L. (2005) J. Biol. Chem. 280, 18265-18273). 5′-Methylthio-Immucillin A (MT-ImmA) and 5′-methylthio-DADMe-Immucillin A (MT-DADMe-ImmA) exhibit slow-onset inhibition with Ki* of 77 and 2 pm, respectively, and were selected for structural analysis as the parent compounds of each class of transition state analogue. The crystal structures of Escherichia coli MTAN complexed with MT-ImmA and MT-DADMe-ImmA were determined to 2.2 Å resolution and compared with the existing MTAN inhibitor complexes. These MTAN-transition state complexes are among the tightest binding enzyme-ligand complexes ever described and analysis of their mode of binding provides extraordinary insight into the structural basis for their affinity. The MTAN-MT-ImmA complex reveals the presence of a new ion pair between the 4′-iminoribitol atom and the nucleophilic water (WAT3) that captures key features of the transition state. Similarly, in the MTAN-MT-DADMe-ImmA complex a favorable hydrogen bond or ion pair interaction between the cationic 1′-pyrrolidine atom and WAT3 is crucial for tight affinity. Distance analysis of the nucleophile and leaving group show that MT-ImmA is a mimic of an early transition state, while MT-DADMe-ImmA is a better mimic of the highly dissociated transition state of E. coli MTAN. A Look at Nucleosidase Transition State Analogue Binding♦Journal of Biological ChemistryVol. 280Issue 18PreviewThe nucleosides, 5′-methylthioadenosine and S-adenosylhomocysteine, are involved in many key cellular reactions such as methylation, polyamine biosynthesis, and methionine recycling. In many pathogenic microbes, both nucleosides are broken down by 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN). Because this enzyme is not present in mammals it is a potential antimicrobial target. As such, several MTAN inhibitors have been developed, including the transition state analogues 5′-methylthio-immucillin A (MT-ImmA) and 5′-methylthio-DADMe-immucillin A (MT-DADMe-ImmA). Full-Text PDF Open Access The nucleosides, 5′-methylthioadenosine (MTA) 1The abbreviations used are: MTA, 5′-methylthioadenosine; SAH, S-adenosylhomocysteine; MTAN, 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase; MTAP, 5′-methylthioadenosine phosphorylase; MT-ImmA, (1S)-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-methylthio-d-ribitol; MT-DADMe-ImmA, (3R,4S)-1-[9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(methylthiomethyl)pyrrolidine; MTT, 5′-methylthiotubercidin; PNP, purine nucleoside phosphorylase; FMA, formycin A; r.m.s.d., root mean square deviation. and S-adenosylhomocysteine (SAH) are molecules involved in key cellular functions such as biological methylation (1Borchardt R.T. Creveling C.R. Ueland P.M. Biological Methylation and Drug Design-Experimental and Clinical Roles of S-Adenosylmethionine. Humana Press, Clifton, NJ1986: 227-238Google Scholar), polyamine biosynthesis (2Raina A. Tuomi K. Pajula R.L. Biochem. J. 1982; 204: 697-703Crossref PubMed Scopus (49) Google Scholar, 3Pajula R.L. Raina A. FEBS Lett. 1979; 99: 343-345Crossref PubMed Scopus (106) Google Scholar), methionine recycling (4Sufrin J.R. Meshnick S.R. Spiess A.J. Garofalo-Hannan J. Pan X.Q. Bacchi C.J. Antimicrob. Agents Chemother. 1995; 39: 2511-2515Crossref PubMed Scopus (59) Google Scholar, 5Riscoe M.K. Ferro A.J. Fitchen J.H. Parasitol. Today. 1989; 5: 330-333Abstract Full Text PDF PubMed Scopus (37) Google Scholar), and bacterial quorum sensing (6Chen X. Schauder S. Potier N. Van Dorsselaer A. Pelczer I. Bassler B.L. Hughson F.M. Nature. 2002; 415: 545-549Crossref PubMed Scopus (1251) Google Scholar, 7Schauder S. Shokat K. Surette M.G. Bassler B.L. Mol. Microbiol. 2001; 41: 463-476Crossref PubMed Scopus (827) Google Scholar). The breakdown of these nucleosides differs in microbial and mammalian systems. In many pathogenic microbes, such as Bacillus anthracis, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis, and Helicobacter pylori, MTA and SAH are catabolized by the dual substrate specific enzyme, MTA/SAH nucleosidase (MTAN). MTAN irreversibly cleaves the glycosidic bond of MTA or SAH to form adenine and 5-methylthioribose or S-ribosylhomocysteine, respectively (8Duerre J.A. J. Biol. Chem. 1962; 237: 3737-3741Abstract Full Text PDF Google Scholar). However, in mammalian systems the nucleosidase is not present and the breakdown of MTA and SAH requires two separate enzymes, MTA phosphorylase (MTAP) (9Pegg A.E. Williams-Ashman H.G. J. Biol. Chem. 1969; 244: 682-693Abstract Full Text PDF PubMed Google Scholar) and SAH hydrolase (10de la Haba G. Cantoni G. J. Biol. Chem. 1959; 234: 603-608Abstract Full Text PDF PubMed Google Scholar), respectively. Given the differences in metabolism, MTA/SAH nucleosidase has been identified and validated as a potential target for the design of broad-spectrum antimicrobials (4Sufrin J.R. Meshnick S.R. Spiess A.J. Garofalo-Hannan J. Pan X.Q. Bacchi C.J. Antimicrob. Agents Chemother. 1995; 39: 2511-2515Crossref PubMed Scopus (59) Google Scholar, 5Riscoe M.K. Ferro A.J. Fitchen J.H. Parasitol. Today. 1989; 5: 330-333Abstract Full Text PDF PubMed Scopus (37) Google Scholar). The structures of MTAN complexed with adenine (MTAN-adenine) (11Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. Structure (Lond.). 2001; 9: 941-953Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar), formycin A (MTAN-FMA) and 5′-methylthiotubercidin (MTAN-MTT) (12Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. J. Biol. Chem. 2003; 278: 8761-8770Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar) have been solved and a comparison of the active site architecture reveals that MTAN is most similar to MTAP (11Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. Structure (Lond.). 2001; 9: 941-953Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 12Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. J. Biol. Chem. 2003; 278: 8761-8770Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 13Lee J.E. Settembre E.C. Cornell K.A. Riscoe M.K. Sufrin J.R. Ealick S.E. Howell P.L. Biochemistry. 2004; 43: 5159-5169Crossref PubMed Scopus Google Scholar). MTAP to the class of purine nucleoside phosphorylases Ealick S.E. Biochem. J. 2002; PubMed Scopus Google Scholar), are proposed to a with the of a ion by the nucleophilic by the (11Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. Structure (Lond.). 2001; 9: 941-953Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, Ealick S.E. Structure (Lond.). Full Text Full Text PDF PubMed Scopus Google Scholar, R.L. Ealick S.E. Biochemistry. PubMed Scopus Google Scholar, D. G. J. Biochem. PubMed Scopus Google Scholar, D. G. PubMed Scopus Google Scholar, Biochemistry. PubMed Scopus Google Scholar, A. Biochemistry. 2004; 43: PubMed Scopus Google Scholar). The structural to the of MTAN, MTAP, and a similar (11Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. Structure (Lond.). 2001; 9: 941-953Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). and inhibitor have the transition for these to D. G. J. Biochem. PubMed Scopus Google Scholar, A. Biochemistry. 2004; 43: PubMed Scopus Google Scholar). S. J. E. Lee, P. L. Howell, and V. L. Schramm, Given the in transition state inhibitors for and MTAP were for their to MTAN. has been inhibitor for MTAP and PNP. the that in a in to a of and in the of Google Scholar). The inhibition of provides a target for the of and J.A. PubMed Scopus Google Scholar). of the tuberculosis, and transition state structures led to the of the Immucillin and DADMe-Immucillin transition state analogues Biochemistry. PubMed Scopus (79) Google Scholar, Biochemistry. PubMed Scopus Google Scholar, A. A. Biochemistry. 2002; 41: PubMed Scopus Google Scholar, K. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, K. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Chem. 2003; PubMed Scopus Google Scholar, A. J. Chem. 2003; PubMed Scopus Google Scholar, Biochemistry. 2001; PubMed Scopus Google Scholar, Biochemistry. 2001; PubMed Scopus Google Scholar). In the the with a to match the state of a dissociated the purine is by a to a bond the of to and for The DADMe-Immucillin inhibitors were with a between the and group to mimic the highly dissociated or bond of the leaving group A. J. Chem. 2003; PubMed Scopus Google Scholar, A. Biochemistry. 2003; PubMed Scopus Google Scholar, A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). In the is to the the to mimic the of the between the and The Immucillin and DADMe-Immucillin class of inhibitors exhibit tight binding with Ki* in the range in and Biochemistry. PubMed Scopus Google Scholar, A. J. Chem. 2003; PubMed Scopus Google Scholar, A. Biochemistry. 2003; PubMed Scopus Google Scholar, A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). the Immucillin and DADMe-Immucillin of transition state analogues were to MTA phosphorylase and Escherichia coli MTA/SAH nucleosidase V. J. K. S. J.E. Howell P.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, V. Biochemistry. 2004; 43: PubMed Scopus Google Scholar, V. J. Chem. 2004; PubMed Scopus Google Scholar). 5′-Methylthio-Immucillin A (MT-ImmA) and 5′-methylthio-DADMe-Immucillin A (MT-DADMe-ImmA) exhibit tight binding in E. coli MTAN with Ki* 77 and 2 pm, respectively V. J. K. S. J.E. Howell P.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). substitutions to the 5′-thio group inhibitors with constants to is of the most inhibitors ever MT-ImmA and MT-DADMe-ImmA were selected for structural analysis as the parent compounds of the two transition state The structures of MTA/SAH nucleosidase complexed with the inhibitors MT-ImmA and MT-DADMe-ImmA have been determined to 2.2 Å of MTAN-MT-ImmA and MTAN-MT-DADMe-ImmA with the determined and structures has a of the between the active site and the inhibitors that for the tight of the transition state The structures that of MT-DADMe-ImmA favorable between the cationic the and the nucleophilic water an favorable hydrogen bond or an ion The structures of MTAN complexed with MT-ImmA and MT-DADMe-ImmA are compared with a structure the complex and and favorable hydrogen bond with with the mimics in the Immucillin of MTAN-MT-ImmA and E. coli MTA/SAH nucleosidase and as described J.E. Cornell K.A. Riscoe M.K. Howell P.L. Biol. 2001; PubMed Scopus Google Scholar). The transition state analogues MT-ImmA and MT-DADMe-ImmA were as V. Biochemistry. 2004; 43: PubMed Scopus Google Scholar). The enzyme to and with MT-ImmA or MT-DADMe-ImmA for 2 were at the MTAN-MT-ImmA were and MTAN-MT-DADMe-ImmA a as in and and nucleosidase crystal in a of at the for The MTAN-MT-DADMe-ImmA crystal to a MT-DADMe-ImmA, and for 2 to in a of were both MTAN-MT-ImmA and MTAN-MT-DADMe-ImmA to 2.2 Å resolution a with and were the Biol. PubMed Scopus Google Scholar). to structure and the Scopus Google Scholar) used to to the to the as as to The are in and of of range and the of the and the mean The is in the to in the resolution in the to in the resolution in the to in the resolution in the to in the resolution in the to in the resolution in the to in the resolution of of water of range and are the and structure the is a of of the validated and the of the and the mean The is in the to in the resolution and are the and structure the is a of of the Open in a new Structure group and constants of the MTAN-MT-ImmA and MTAN-MT-DADMe-ImmA are with the (12Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. J. Biol. Chem. 2003; 278: 8761-8770Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar), to the structures each structure the water and inhibitor molecules were to a of in P. J. Biol. PubMed Scopus Google Scholar), between and 2.2 Å with each as a and were of in J. Biol. PubMed Scopus Google Scholar) and A. A. PubMed Scopus Google Scholar) and with an and were The of the by the in and water molecules and to the MT-ImmA or MT-DADMe-ImmA The MT-ImmA were by the of MTA the Biol. PubMed Scopus Google Scholar). The for MT-DADMe-ImmA were the The and were the 1995; Scholar). molecules with and and were while the in the of water and inhibitor molecules into the of and in were of the enzyme in the of of the The of the were in a of and to in A and in were to into the The of and in both MTAN-MT-DADMe-ImmA were to in two and were and as The MTAN-MT-ImmA and MTAN-MT-DADMe-ImmA structures were to and and and respectively. of the structures in J. Google Scholar, J. G. PubMed Scopus Google Scholar) and P. J. Biol. PubMed Scopus Google Scholar) with into the of the The are in I. of MTA/SAH nucleosidase structures were by of selected in the the by G. The used in the of the were and for MTA and of the and the for MTA, MT-ImmA, and MT-DADMe-ImmA were in the constants in for were at of for the by in MTA, in MT-ImmA and in that the of MT-DADMe-ImmA is in for were at for the of the with to the were for MTA and both and cationic of MT-ImmA and are to are in and the are to in water the are The structures of MTAN-MT-ImmA and MTAN-MT-DADMe-ImmA are similar to the structures of MTAN complexed with or (12Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. J. Biol. Chem. 2003; 278: 8761-8770Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). The enzyme is a and active site (11Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. Structure (Lond.). 2001; 9: 941-953Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). an structure with a and a The is by and The is of the and and the between and The nucleosidase active site has to the and of the substrate MTAN-MT-ImmA and MTAN-MT-DADMe-ImmA were at and respectively, the are not to MTAN has been to active at K.A. Riscoe M.K. Biochem. PubMed Scopus Google of and of the purine and site The and MTAN-MT-DADMe-ImmA structures are in and respectively. of comparison and were In and with are a site for MTAN-MT-ImmA and MTAN-MT-DADMe-ImmA complexes. or hydrogen with in a are in and in and the to hydrogen in A and respectively. in the MT-ImmA and MT-DADMe-ImmA structures to the structure are The structure with solved (12Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. J. Biol. Chem. 2003; 278: 8761-8770Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar), and the to a comparison with MT-ImmA and The active site is with 12Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. J. Biol. Chem. 2003; 278: 8761-8770Abstract Full Text Full Text PDF PubMed Scopus (54) Google of Biological with MT-ImmA identified in the in the active of both In the the and of hydrogen to the and of the of MT-ImmA, respectively a and is into a by hydrogen the of and the of hydrogen are the and of to the and The and of are Å the of the A and this with the The MT-ImmA nucleoside to MTAN is in a to the The the bond is to the in the and structures (12Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. J. Biol. Chem. 2003; 278: 8761-8770Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). In the this is proposed to the bond to bond In the and and the nucleophilic water (WAT3) the and The is by a hydrogen bond between and and the and group of respectively. a hydrogen bond between and the and the of the and the The group of MT-ImmA two hydrogen to the of and the nucleophilic WAT3 WAT3 is by a of hydrogen to the group of the group of and the and The has a The group is by and and and and a and the with an bond of and to a is similar to the in the structure (12Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. J. Biol. Chem. 2003; 278: 8761-8770Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar) and in the MTA crystal structure N. Google Scholar). However, of MTA have that in a of are present with a of the Biochemistry. 2002; 41: PubMed Scopus Google Scholar). with for the MT-DADMe-ImmA in the active of both The between the and the are to in the MTAN-MT-ImmA the MT-ImmA the MT-DADMe-ImmA inhibitor is to MTAN in a the presence of the between the and the the to compared with in the and The binding of the is as this a As a the the mimic with the is and The two hydrogen to the of and the nucleophilic water while WAT3 with the As for the and MT-ImmA complexed WAT3 is by hydrogen to the group of the of and the of The of the and of the The is in a and not the group of MT-DADMe-ImmA with a and the with the in the MTAN-MT-ImmA The is with a to the has a in is an of the MTAN-MT-ImmA to the in the and MTAN-MT-ImmA MT-DADMe-ImmA is of the tightest MTAN transition state analogues with a Ki* of 2 inhibitor better MT-ImmA 77 and better K.A. Riscoe M.K. Biochem. PubMed Scopus Google Scholar). the tight binding of MT-ImmA and MT-DADMe-ImmA, a of and structures The reveals between structures in of The root mean square between in the and the MTAN-MT-ImmA and MTAN-MT-DADMe-ImmA are and respectively. The between the MTAN-MT-ImmA and MTAN-MT-DADMe-ImmA is of the and reveals that the are However, are differences in the of the nucleophilic water (WAT3) and of the inhibitor that for the tight binding of the transition state of for hydrogen bond differences between MT-ImmA and and the are and for the differences in binding However, is transition state that for the binding of The substrate is a and is interaction between the nucleophilic water and the as by the and in A and respectively In these two a to the presence of two The 4′-iminoribitol group of MT-ImmA has a that is cationic in the active of A. A. Biochemistry. 2003; PubMed Scopus Google Scholar). mimics the at this the nucleophilic water the 4′-iminoribitol group is that this interaction is a hydrogen J. A.J. P. P. G. Nature. PubMed Scopus Google Scholar) has that a hydrogen bond between and for and is a of in The of a hydrogen bond not binding to the in for MT-ImmA compared with interaction between WAT3 and the 4′-iminoribitol group the affinity. water is not a nucleophile and is for to The and of are in to The water nucleophile a ion pair with the 4′-iminoribitol In the WAT3 not an interaction to the The of the purine atom with a a at and the of at the for is in the of the the binding in MT-ImmA by a and 4′-iminoribitol or an state to a an binding of and a of this is the binding is to for the of MT-ImmA binding of the 4′-iminoribitol in MT-ImmA an ion pair is in the complex V. Biochemistry. 2004; 43: PubMed Scopus Google Scholar). The between the and the 4′-iminoribitol to binding to for the in affinity. for in the atom and the is by a The of the hydrogen to and The of the to the two hydrogen the to and that MT-DADMe-ImmA to MTAN MT-ImmA, in binding is A of the transition state structures reveals similar hydrogen bond and to in and The inhibition for by two features of the transition state analogue. The of the 1′-pyrrolidine is and cationic at The presence of the cationic atom and the of the a better of the transition state features by the nucleophilic water to to and Å of the 1′-pyrrolidine in A and respectively. WAT3 and Å to the nucleoside in the and MTAN-MT-ImmA respectively that WAT3 is and a ion pair with the binding to Å in a of binding is to the in binding between MT-DADMe-ImmA and the interaction between WAT3 and the 1′-pyrrolidine an favorable hydrogen bond favorable hydrogen have between the two the In the between the two a the of their Biochem. PubMed Scopus Google Scholar). These of hydrogen for binding of to and have been to a in transition and in the or of the of enzyme reactions Biochem. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J.A. Biochemistry. PubMed Scopus Google Scholar). The presence of an favorable hydrogen bond the in the Ki* 77 to 2 between MT-ImmA and such as MTA or SAH in have been to exhibit with the the Biochemistry. 2002; 41: PubMed Scopus Google Scholar). In crystal structures of MTAP and MTAN, with the of the nucleoside are in a (12Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. J. Biol. Chem. 2003; 278: 8761-8770Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 13Lee J.E. Settembre E.C. Cornell K.A. Riscoe M.K. Sufrin J.R. Ealick S.E. Howell P.L. Biochemistry. 2004; 43: 5159-5169Crossref PubMed Scopus Google Scholar, Ealick S.E. Structure (Lond.). Full Text Full Text PDF PubMed Scopus Google Scholar, V. Biochemistry. 2004; 43: PubMed Scopus Google Scholar). In the of the between the and and the of the to the MT-DADMe-ImmA to a The in in the MTAN-MT-DADMe-ImmA structure to the to binding of the the for MTA and MT-ImmA as as cationic MT-DADMe-ImmA in that the for MTA is in with and cationic MT-ImmA both have their in the while the of MT-DADMe-ImmA an at the transition state is a ion with an of the at the transition state, that the mimic of the transition state, both in and is the is to to 2 in binding for both the MT-ImmA and MT-DADMe-ImmA A similar analysis of the of MTA, MT-ImmA and MT-DADMe-ImmA and cationic reveals are as as 2.2 for MTA are for MT-ImmA and and that MT-ImmA and MT-DADMe-ImmA to the enzyme better the MTA, by the in transition state for MT-DADMe-ImmA, is the cationic mimic of the transition state. The of the cationic of the MT-DADMe-ImmA is in the crystal structure the ion pair between the water (WAT3) and the of MT-DADMe-ImmA is in the MT-ImmA complex and is a for of the DADMe-Immucillin class of femtomolar inhibition by aromatic substitutions to the of V. J. K. S. J.E. Howell P.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The most inhibitor is with a Ki* a crystal structure complex with this inhibitor has not been the for tight binding is to similar to The of the binding is to an ion pair or favorable hydrogen bond interaction between the nucleophilic water and the The of a to the 5′-thio group or to and in the binding PubMed Scopus Google Scholar). and to the to binding to for the binding MT-DADMe-ImmA of MTA/SAH nucleosidase is an hydrolase that the Given the structural between MTAN and the of nucleoside the nucleosidase is proposed to a (11Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. Structure (Lond.). 2001; 9: 941-953Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 12Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. J. Biol. Chem. 2003; 278: 8761-8770Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). The of the bond of MTA and SAH is proposed to a nucleophilic are two in the for The is the and to the of the while the is and to the nucleophilic by In and P. purine nucleoside phosphorylase have that these reactions a with a dissociated while in nucleoside a transition state is of the group A. Biochemistry. 2004; 43: PubMed Scopus Google Scholar, Biochemistry. PubMed Scopus Google Scholar). MTAN a transition state structure with a leaving group and to the As a the MTAN is by two and a for the The or complex by the structure (12Lee J.E. Cornell K.A. Riscoe M.K. Howell P.L. J. Biol. Chem. 2003; 278: 8761-8770Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). In this the nucleophile is Å the and the bond is of Å A analysis of the MTAN transition state structure with bond is the bond is Å at the transition As the bond a of the atom and the of the In the between the and with most of the Chem. 2002; Scholar). In the ion a the the between the and the nucleophilic water the to The complex show a to that is dissociated and the of a bond between the water and as in the complex of A. Biochemistry. 2003; PubMed Scopus Google Scholar). MT-ImmA to MTAN has a bond and a of Å between WAT3 and the The MT-DADMe-ImmA to MTAN has an the atom to the to the and a Å between the nucleophile and the 1′-pyrrolidine the bond to the leaving group and the to the nucleophile MT-ImmA the and a mimic of an early transition state The between the and the leaving group MT-DADMe-ImmA the MT-ImmA and a mimic to a highly dissociated transition state. The and of compounds are the most transition state analogues for MTA/SAH MT-DADMe-ImmA of the These inhibitors were to mimic the ion in the transition state The crystal structures of E. coli MTAN complexed with MT-ImmA and MT-DADMe-ImmA have a comparison to MTAN structures and a structural basis for the tight The tight binding of MT-ImmA and MT-DADMe-ImmA to a key interaction between the of the and the nucleophilic In MTAN-MT-ImmA this interaction is an ion while in MTAN-MT-DADMe-ImmA an ion pair or an favorable hydrogen bond provides the binding for analysis of the between the and the and nucleophilic water reveals that MT-ImmA and MT-DADMe-ImmA are mimics of an early and highly dissociated transition state of E. coli MTAN, respectively.

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