Molecule Information

General Information of the Molecule (ID: Mol04086)

• Name: Adenosylmethionine decarboxylase 1 (AMD1) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: AMD1
• Gene ID: 262
• Location: chr6:110874770-110898879[+]
• Sequence:
  MEAAHFFEGTEKLLEVWFSRQQPDANQGSGDLRTIPRSEWDILLKDVQCSIISVTKTDKQ
  EAYVLSESSMFVSKRRFILKTCGTTLLLKALVPLLKLARDYSGFDSIQSFFYSRKNFMKP
  SHQGYPHRNFQEEIEFLNAIFPNGAAYCMGRMNSDCWYLYTLDFPESRVISQPDQTLEIL
  MSELDPAVMDQFYMKDGVTAKDVTRESGIRDLIPGSVIDATMFNPCGYSMNGMKSDGTYW
  TIHITPEPEFSYVSFETNLSQTSYDDLIRKVVEVFKPGKFVTTLFVNQSSKCRTVLASPQ
  KIEGFKRLDCQSAMFNDYNFVFTSFAKKQQQQQS
• 3D-structure: PDB ID: 3H0W; Classification: Lyase; Method: X-ray diffraction; Resolution: 1.81 Å
• Function: Essential for biosynthesis of the polyamines spermidine and spermine. Promotes maintenance and self-renewal of embryonic stem cells, by maintaining spermine levels. .
• Uniprot ID: DCAM_HUMAN
• Ensembl ID: ENSG00000123505
• HGNC ID: HGNC:457

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

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

Vemurafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Melanoma [ICD-11: 2C30.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Hs294T cells; Skin; Homo sapiens (Human); CVCL_0331
• In Vitro Model: SK-MEL-28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reduces vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro cell line models and in vivo in a xenograft model. Polyamine biosynthesis signature is associated with poor prognosis and shorter progression free survival after BRAF/MAPK inhibitor treatment in melanoma cohorts, highlighting the clinical relevance of our findings.

References

• Ref 1: Polyamine and EIF5A hypusination downstream of c-Myc confers targeted therapy resistance in BRAF mutant melanoma. Mol Cancer. 2024 Jul 4;23(1):136.