6dz0

From Proteopedia

(Difference between revisions)

Revision as of 07:47, 10 April 2019

Crystal structure of human 5'-deoxy-5'-methylthioadenosine phosphorylase in complex with (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-((pent-4-yn-1-ylthio)methyl)pyrrolidin-3-ol

Structural highlights

6dz0 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Gene:	MTAP, MSAP (HUMAN)
Activity:	S-methyl-5'-thioadenosine phosphorylase, with EC number 2.4.2.28
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[MTAP_HUMAN] Defects in MTAP are the cause of diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH) [MIM:112250]. An autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. Some patients show a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. Note=DMSMFH causing mutations found in MTAP exon 9 result in exon skipping and dysregulated alternative splicing of all MTAP isoforms (PubMed:22464254).^[1] Note=Loss of MTAP activity may play a role in human cancer. MTAP loss has been reported in a number of cancers, including osteosarcoma, malignant melanoma and gastric cancer.[HAMAP-Rule:MF_03155]

Function

[MTAP_HUMAN] Catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S-adenosylmethionine. Has broad substrate specificity with 6-aminopurine nucleosides as preferred substrates.^[2]

Publication Abstract from PubMed

Bacterial 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzes the hydrolysis of adenine from S-methyl-5'-thioadenosine (MTA) and S-adenosyl L-homocysteine (SAH) to form S-methyl-5'-thioribose (MTR) and S-ribosyl-L-homocysteine (SRH), respectively. The MTANs are involved in quorum sensing pathways and hydrolyze MTA to metabolites for recycling to S-adenosylmethionine (SAM). A few bacterial species use the futalosine pathway for menaquinone synthesis and in these, MTAN catalyzes an essential step, making it a candidate for species-specific antibiotic development. Helicobacter pylori uses the unusual futalosine pathway for menaquinone biosynthesis and the MTAN from H. pylori (HpMTAN) is a target for antibiotic development. Human 5'-methylthioadenosine phosphorylase (MTAP) catalyzes phosphorylation reactions with substrate specificity similar to the bacterial MTANs. It plays a metabolic role in the salvage of MTA for SAM salvage pathways and has been reported to be an anticancer target. Transition state analogues designed for HpMTAN and for MTAP have been reported and show significant overlap in specificity. It is desirable to design transition state analogues specific for the HpMTAN as an antibiotic in the treatment of H. pylori infections. Fifteen unique transition state analogues are described here and are used to explore the inhibitor specificity and the structural scaffolds for HpMTAN and MTAP. Several inhibitors are transition-state analogues of H. pylori MTAN with dissociation constants in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. X-ray crystal structures of HpMTAN and MTAP show inhibitors of HpMTAN extending through a hydrophobic channel to the protein surface, while the more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the catalytic site phosphate nucleophile.

"Selective inhibitors of H. pylori methylthioadenosine nucleosidase and human methylthioadenosine phosphorylase".,Harijan RK, Hoff O, Ducati RG, Firestone RS, Hirsch BM, Evans GB, Schramm VL, Tyler PC J Med Chem. 2019 Mar 12. doi: 10.1021/acs.jmedchem.8b01642. PMID:30860833^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Camacho-Vanegas O, Camacho SC, Till J, Miranda-Lorenzo I, Terzo E, Ramirez MC, Schramm V, Cordovano G, Watts G, Mehta S, Kimonis V, Hoch B, Philibert KD, Raabe CA, Bishop DF, Glucksman MJ, Martignetti JA. Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts. Am J Hum Genet. 2012 Apr 6;90(4):614-27. doi: 10.1016/j.ajhg.2012.02.024. Epub, 2012 Mar 29. PMID:22464254 doi:10.1016/j.ajhg.2012.02.024
↑ Della Ragione F, Carteni-Farina M, Gragnaniello V, Schettino MI, Zappia V. Purification and characterization of 5'-deoxy-5'-methylthioadenosine phosphorylase from human placenta. J Biol Chem. 1986 Sep 15;261(26):12324-9. PMID:3091600
↑ Harijan RK, Hoff O, Ducati RG, Firestone RS, Hirsch BM, Evans GB, Schramm VL, Tyler PC. "Selective inhibitors of H. pylori methylthioadenosine nucleosidase and human methylthioadenosine phosphorylase". J Med Chem. 2019 Mar 12. doi: 10.1021/acs.jmedchem.8b01642. PMID:30860833 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01642

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6dz0"

@@ Line 3: / Line 3: @@
 <StructureSection load='6dz0' size='340' side='right'caption='[[6dz0]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6dz0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DZ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DZ0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6dz0]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DZ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DZ0 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=OS3:(3R,4S)-1-[(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl]-4-{[(pent-4-yn-1-yl)sulfanyl]methyl}pyrrolidin-3-ol'>OS3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MTAP, MSAP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/S-methyl-5'-thioadenosine_phosphorylase S-methyl-5'-thioadenosine phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.28 2.4.2.28] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dz0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dz0 OCA], [http://pdbe.org/6dz0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dz0 RCSB], [http://www.ebi.ac.uk/pdbsum/6dz0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dz0 ProSAT]</span></td></tr>
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: S-methyl-5'-thioadenosine phosphorylase]]

6dz0

From Proteopedia

Revision as of 07:47, 10 April 2019

Crystal structure of human 5'-deoxy-5'-methylthioadenosine phosphorylase in complex with (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-((pent-4-yn-1-ylthio)methyl)pyrrolidin-3-ol

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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