title: Substrate channeling between the human dihydrofolate reductase and thymidylate synthase.
abstract: In vivo, as an advanced catalytic strategy, transient non-covalently bound multi-enzyme complexes can be formed to facilitate the relay of substrates, i. e. substrate channeling, between sequential enzymatic reactions and to enhance the throughput of multi-step enzymatic pathways. The human thymidylate synthase and dihydrofolate reductase catalyze two consecutive reactions in the folate metabolism pathway, and experiments have shown that they are very likely to bind in the same multi-enzyme complex in vivo. While reports on the protozoa thymidylate synthase-dihydrofolate reductase bifunctional enzyme give substantial evidences of substrate channeling along a surface "electrostatic highway," attention has not been paid to whether the human thymidylate synthase and dihydrofolate reductase, if they are in contact with each other in the multi-enzyme complex, are capable of substrate channeling employing surface electrostatics. This work utilizes protein-protein docking, electrostatics calculations, and Brownian dynamics to explore the existence and mechanism of the substrate channeling between the human thymidylate synthase and dihydrofolate reductase. The results show that the bound human thymidylate synthase and dihydrofolate reductase are capable of substrate channeling and the formation of the surface "electrostatic highway." The substrate channeling efficiency between the two can be reasonably high and comparable to that of the protozoa.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, 92037.
authors.forename: Nuo
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, 92037.|Department of Pharmacology, University of California San Diego, La Jolla, California, 92037.|Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, 92037.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D055162:Biocatalysis; D005492:Folic Acid / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D009097:Multienzyme Complexes / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D012984:Software; D055672:Static Electricity; D013379:Substrate Specificity; D013499:Surface Properties; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D009097:Multienzyme Complexes; C056930:thymidylate synthase-dihydrofolate reductase; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase
keywords: bifunctional DHFR-TS; dihydrofolate reductase; electrostatic channeling; folate; metabolon; one-carbon metabolism; substrate channeling; thymidylate synthase