Molecule Information

General Information of the Molecule (ID: Mol01145)

• Name: Cardiolipin synthase (CLS) ,Homo sapiens
• Synonyms: cls; CGZ46_07295; DAI13_08110; EU507_02395; H9Q64_02915
• Molecule Type: Protein
• Gene Name: cls
• Sequence:
  MKIFVWILLFLLVINVIAALITVFRKPRSISSVLAWMMTLIFLPGIGFIIYLFCGRGIDG
  QEVFKLSDDEKQMVQRIKEKVDVDNKKAGRDKRYDLLYDAKVLNRYFRNMDASPLAKRNS
  LQLFTDGQEKFQALFEDIRAAKETVHVEYYAFFNDTIGNQFLDVLIEKLHEGVEVYLIYD
  PWGSPGANKKFFARYVDAGGKVAPFITSRDMIRKTRLNYHLHRKIVVIDGKIGWTGGFNV
  GDQYLNVTEKFGYWRDTHIRLVGTAVFSLQEIFIMDWNASVKYPEERMTYHEKYFKLPED
  HEVEHLSLQVVSDGPDSEEEILKSGFVRMIFSAEKSVWIQTPYLIPDDSMINALLVAVRS
  GVDVRIMIPCMPDHPFIYRATQYYANYLHKRGIKIYIYDSGFIHAKTMVIDDELAMVGTT
  NQDIRSYSLNFEVSTFIYNPDIAWMLAQVFEEDIEKSVLLTDEIIKKQGYWLRFKQNFSR
  LLSPVL
• Function: Catalyzes the reversible phosphatidyl group transfer from one phosphatidylglycerol molecule to another to form cardiolipin (CL) (diphosphatidylglycerol) and glycerol.
• Uniprot ID: A0A246M4D0_ENTFL

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

Type(s) of Resistant Mechanism of This Molecule

  DISM: Drug Inactivation by Structure Modification

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Cytarabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Leukemia [1]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Resistant Drug: Cytarabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CMPD deaminates cytarabine-monophosphate to arabinosyl-uracil-monophosphate. A crucial role for this latter enzyme has been suggested in the metabolism of cytarabine-monophosphate in T-lymphoblastic leukemia.

Disease Class: Lymphoma [1]

• Resistant Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Resistant Drug: Cytarabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CMPD deaminates cytarabine-monophosphate to arabinosyl-uracil-monophosphate. A crucial role for this latter enzyme has been suggested in the metabolism of cytarabine-monophosphate in T-lymphoblastic leukemia.

Daptomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Staphylococcus aureus infection [2], [3], [4]

• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Resistant Drug: Daptomycin
• Molecule Alteration: Missense mutation; p.H215R
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecium S447; 1134840
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Daptomycin (DAP) resistance in enterococci has been linked to mutations in genes that alter the cell envelope stress response (CESR) (liaFSR) and changes in enzymes that directly affect phospholipid homeostasis, and these changes may alter membrane composition, such as that of cardiolipin synthase (Cls).A comparison of the catalytic activities of E. faecium Cls447a to those of Cls447aH215R and Cls447aR218Q shows that mutations associated with DAP resistance increase Cls activity.

Disease Class: Right-sided endocarditis [2], [3], [4]

• Resistant Disease: Right-sided endocarditis [ICD-11: BB41.0]
• Resistant Drug: Daptomycin
• Molecule Alteration: Missense mutation; p.R218Q
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecium S447; 1134840
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Daptomycin (DAP) resistance in enterococci has been linked to mutations in genes that alter the cell envelope stress response (CESR) (liaFSR) and changes in enzymes that directly affect phospholipid homeostasis, and these changes may alter membrane composition, such as that of cardiolipin synthase (Cls).A comparison of the catalytic activities of E. faecium Cls447a to those of Cls447aH215R and Cls447aR218Q shows that mutations associated with DAP resistance increase Cls activity.

References

• Ref 1: Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers. Cancers (Basel). 2021 Feb 25;13(5):966. doi: 10.3390/cancers13050966.
• Ref 2: Genetic basis for in vivo daptomycin resistance in enterococci. N Engl J Med. 2011 Sep 8;365(10):892-900. doi: 10.1056/NEJMoa1011138.
• Ref 3: Genotypic and phenotypic evaluation of the evolution of high-level daptomycin nonsusceptibility in vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother. 2012 Nov;56(11):6051-3. doi: 10.1128/AAC.01318-12. Epub 2012 Sep 4.
• Ref 4: Biochemical characterization of cardiolipin synthase mutations associated with daptomycin resistance in enterococci. Antimicrob Agents Chemother. 2013 Jan;57(1):289-96. doi: 10.1128/AAC.01743-12. Epub 2012 Oct 31.