Molecule Information

General Information of the Molecule (ID: Mol02063)

• Name: S-adenosylmethionine synthase (METK) ,Leishmania infantum
• Synonyms: METK; MAT2
• Molecule Type: Protein
• Gene Name: METK
• Sequence:
  MSVHSILFSSEHVTEGHPDKLCDQVSDAVLDACLAGDPFSKVACESCAKTGMVMVFGEIT
  TKAVLDYQKIVRNTIKDIGFDSADKGLDYESCNVLVAIEQQSPDICQGLGNFDSEDLGAG
  DQGMMFGYATDETETLMPLTYELARGLAKKYSELRRSGSLEWARPDAKTQVTVEYDYDTR
  EGKQVLTPKRVAVVLISAQHDEHVTNDKISVDLMEKVIKAVIPANMLDAETKYWLNPSGR
  FVRGGPHGDAGLTGRKIIVDTYGGWGAHGGGAFSGKDPSKVDRSAAYAARWIAKSIVAGG
  LARRCLVQLAYAIGVAEPLSMHVETYGTGKYDDAKLLEIVKQNFKLRPYDIIQELNLRRP
  IYYDTSRFGHFGRKDELGTGGFTWEVPKKMVE
• Function: Catalyzes the formation of S-adenosylmethionine from methionine and ATP. The reaction comprises two steps that are both catalyzed by the same enzyme: formation of S-adenosylmethionine (AdoMet) and triphosphate, and subsequent hydrolysis of the triphosphate.
• Uniprot ID: METK_LEIIN

Kingdom: N.A.
Phylum: Euglenozoa
Class: Kinetoplastea
Order: Trypanosomatida
Family: Trypanosomatidae
Genus: Leishmania
Species: Leishmania infantum

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Allopurinol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Visceral leishmaniasis [1]

• Resistant Disease: Visceral leishmaniasis [ICD-11: 1F54.0]
• Resistant Drug: Allopurinol
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Leishmania infantum strain; 5671
• Experiment for Molecule Alteration: Quantitative PCR assays
• Mechanism Description: A reduction in copy number for LinJ.30.3560, encoding the S-adenosylmethionine synthetase (METK) gene, was found in two resistant clinical isolates and four induced resistant clonal strains. Using quantitative real time PCR, this reduction in METK copy number was also found in three additional resistant clinical isolates. Since allopurinol can be incorporated into energetic nucleotides such as ATP it may be that such allopurinol containing nucleotides inhibit S-adenosylmethionine synthetase or are utilized by it, producing faulty products, which in turn inhibit the parasite's growth. Down-regulation of S-adenosylmethionine synthetase in resistant strains may reduce the levels of such faulty products.

References

• Ref 1: Resistance of Leishmania infantum to allopurinol is associated with chromosome and gene copy number variations including decrease in the S-adenosylmethionine synthetase (METK) gene copy number .Int J Parasitol Drugs Drug Resist. 2018 Dec;8(3):403-410. doi: 10.1016/j.ijpddr.2018.08.002. Epub 2018 Aug 23. 10.1016/j.ijpddr.2018.08.002