PDBsum entry 1sd1

Transferase

PDB id

1sd1

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Contents

			Protein chain

					268 a.a. *

			Ligands

					FMC

			Waters ×249

* Residue conservation analysis

PDB id:

1sd1

Links

Name:

Transferase

Title:

Structure of human 5'-deoxy-5'-methylthioadenosine phosphorylase complexed with formycin a

Structure:

5'-methylthioadenosine phosphorylase. Chain: a. Synonym: mta phosphorylase, mtapase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mtap, msap. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Trimer (from PDB file)

Resolution:

2.03Å

R-factor:

0.180

R-free:

0.198

Authors:

J.E.Lee,E.C.Settembre,K.A.Cornell,M.K.Riscoe,J.R.Sufrin,S.E.Ealick, P.L.Howell

Key ref:

J.E.Lee et al. (2004). Structural comparison of MTA phosphorylase and MTA/AdoHcy nucleosidase explains substrate preferences and identifies regions exploitable for inhibitor design. Biochemistry, 43, 5159-5169. PubMed id: 15122881 DOI: 10.1021/bi035492h

Date:

12-Feb-04

Release date:

18-May-04

PROCHECK

	Headers

	References

Protein chain

Q13126 (MTAP_HUMAN) - S-methyl-5'-thioadenosine phosphorylase from Homo sapiens

Seq: Struc:					283 a.a. 268 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.2.4.2.28 - S-methyl-5'-thioadenosine phosphorylase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

S-methyl-5'-thioadenosine + phosphate = 5-(methylsulfanyl)-alpha-D-ribose 1-phosphate + adenine

S-methyl-5'-thioadenosine

phosphate
Bound ligand (Het Group name = FMC)
matches with 50.00% similarity

5-(methylsulfanyl)-alpha-D-ribose 1-phosphate

adenine

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/bi035492h	Biochemistry 43:5159-5169 (2004)
PubMed id: 15122881

Structural comparison of MTA phosphorylase and MTA/AdoHcy nucleosidase explains substrate preferences and identifies regions exploitable for inhibitor design.
J.E.Lee, E.C.Settembre, K.A.Cornell, M.K.Riscoe, J.R.Sufrin, S.E.Ealick, P.L.Howell.

ABSTRACT

The development of new and effective antiprotozoal drugs has been a difficult challenge because of the close similarity of the metabolic pathways between microbial and mammalian systems. 5'-Methylthioadenosine/S-adenosylhomocysteine (MTA/AdoHcy) nucleosidase is thought to be an ideal target for therapeutic drug design as the enzyme is present in many microbes but not in mammals. MTA/AdoHcy nucleosidase (MTAN) irreversibly depurinates MTA or AdoHcy to form adenine and the corresponding thioribose. The inhibition of MTAN leads to a buildup of toxic byproducts that affect various microbial pathways such as quorum sensing, biological methylation, polyamine biosynthesis, and methionine recycling. The design of nucleosidase-specific inhibitors is complicated by its structural similarity to the human MTA phosphorylase (MTAP). The crystal structures of human MTAP complexed with formycin A and 5'-methylthiotubercidin have been solved to 2.0 and 2.1 A resolution, respectively. Comparisons of the MTAP and MTAN inhibitor complexes reveal size and electrostatic potential differences in the purine, ribose, and 5'-alkylthio binding sites, which account for the substrate specificity and reactions catalyzed. In addition, the differences between the two enzymes have allowed the identification of exploitable regions that can be targeted for the development of high-affinity nucleosidase-specific inhibitors. Sequence alignments of Escherichia coli MTAN, human MTAP, and plant MTA nucleosidases also reveal potential structural changes to the 5'-alkylthio binding site that account for the substrate preference of plant MTA nucleosidases.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21166890

N.Parveen, and K.A.Cornell (2011).
Methylthioadenosine/S-adenosylhomocysteine nucleosidase, a critical enzyme for bacterial metabolism.

Mol Microbiol, 79, 7.

20954236

D.R.Ronning, N.M.Iacopelli, and V.Mishra (2010).
Enzyme-ligand interactions that drive active site rearrangements in the Helicobacter pylori 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase.

Protein Sci, 19, 2498-2510.

PDB codes:

3nm4 3nm5 3nm6

19946895

E.Albers (2009).
Metabolic characteristics and importance of the universal methionine salvage pathway recycling methionine from 5'-methylthioadenosine.

IUBMB Life, 61, 1132-1142.

19376840

K.A.Cornell, S.Primus, J.A.Martinez, and N.Parveen (2009).
Assessment of methylthioadenosine/S-adenosylhomocysteine nucleosidases of Borrelia burgdorferi as targets for novel antimicrobials using a novel high-throughput method.

J Antimicrob Chemother, 63, 1163-1172.

16909418

E.Y.Park, S.I.Oh, M.J.Nam, J.S.Shin, K.N.Kim, and H.K.Song (2006).
Crystal structure of 5'-methylthioadenosine nucleosidase from Arabidopsis thaliana at 1.5-A resolution.

Proteins, 65, 519-523.

PDB code:

2h8g

16904326

S.L.Mosley, B.A.Bakke, J.M.Sadler, N.K.Sunkara, K.M.Dorgan, Z.S.Zhou, and K.L.Seley-Radtke (2006).
Carbocyclic pyrimidine nucleosides as inhibitors of S-adenosylhomocysteine hydrolase.

Bioorg Med Chem, 14, 7967-7971.

15864263

A.Vendeville, K.Winzer, K.Heurlier, C.M.Tang, and K.R.Hardie (2005).
Making 'sense' of metabolism: autoinducer-2, LuxS and pathogenic bacteria.

Nat Rev Microbiol, 3, 383-396.

15911379

E.Choi-Rhee, and J.E.Cronan (2005).
A nucleosidase required for in vivo function of the S-adenosyl-L-methionine radical enzyme, biotin synthase.

Chem Biol, 12, 589-593.

15746096

J.E.Lee, V.Singh, G.B.Evans, P.C.Tyler, R.H.Furneaux, K.A.Cornell, M.K.Riscoe, V.L.Schramm, and P.L.Howell (2005).
Structural rationale for the affinity of pico- and femtomolar transition state analogues of Escherichia coli 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase.

J Biol Chem, 280, 18274-18282.

PDB codes:

1y6q 1y6r

15749708

V.Singh, G.B.Evans, D.H.Lenz, J.M.Mason, K.Clinch, S.Mee, G.F.Painter, P.C.Tyler, R.H.Furneaux, J.E.Lee, P.L.Howell, and V.L.Schramm (2005).
Femtomolar transition state analogue inhibitors of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Escherichia coli.

J Biol Chem, 280, 18265-18273.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.