Molecule Information

General Information of the Molecule (ID: Mol02003)

• Name: D-alanine--D-alanine ligase (DDL) ,Mycobacterium tuberculosis
• Synonyms: ddl; ddlA; Rv2981c; MTCY349.06
• Molecule Type: Protein
• Gene Name: DDL
• Gene ID: 888415
• Sequence:
  MSANDRRDRRVRVAVVFGGRSNEHAISCVSAGSILRNLDSRRFDVIAVGITPAGSWVLTD
  ANPDALTITNRELPQVKSGSGTELALPADPRRGGQLVSLPPGAGEVLESVDVVFPVLHGP
  YGEDGTIQGLLELAGVPYVGAGVLASAVGMDKEFTKKLLAADGLPVGAYAVLRPPRSTLH
  RQECERLGLPVFVKPARGGSSIGVSRVSSWDQLPAAVARARRHDPKVIVEAAISGRELEC
  GVLEMPDGTLEASTLGEIRVAGVRGREDSFYDFATKYLDDAAELDVPAKVDDQVAEAIRQ
  LAIRAFAAIDCRGLARVDFFLTDDGPVINEINTMPGFTTISMYPRMWAASGVDYPTLLAT
  MIETTLARGVGLH
• 3D-structure: PDB ID: 3LWB; Classification: Ligase; Method: X-ray diffraction; Resolution: 2.10 Å
• Function: Catalyzes the ATP-driven ligation of two D-alanine molecules to form the D-alanyl-D-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis.
• Uniprot ID: DDL_MYCTU

Kingdom: N.A.
Phylum: Actinobacteria
Class: Actinomycetia
Order: 85007
Family: Mycobacteriaceae
Genus: Mycobacterium
Species: Mycobacterium tuberculosis

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

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

Cycloserine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Tuberculosis [ICD-11: 1B10.0] [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Cycloserine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: STK11 KO cells; Fetal kidney; Homo sapiens (Human); CVCL_B3IE
• Experiment for Drug Resistance: Drug susceptibility testing
• Mechanism Description: Since D-cycloserine is a structural analogue of D-alanine, enzymes with substrates of D-alanine are the drug targets of D-cycloserine in mycobacteria. These enzymes include D-alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl), which are required for the synthesis of peptidoglycan in the mycobacterial cell wall. Overexpression of alr and ddl has been shown to cause resistance to D-cycloserine in Mycobacterium smegmatis. Moreover, SNPs in these genes were also found in resistant Mycobacterium tuberculosis. Consistent with the cell-wall peptidoglycan being a target of D-cycloserine, previous studies have shown that D-cycloserine competitively inhibits both Alr and Ddl. However, a more recent metabolomic study showed that Ddl is a primary target of D-cycloserine and is preferentially inhibited over Alr in M. tuberculosis.

References

• Ref 1: Identification of novel mutations associated with cycloserine resistance in Mycobacterium tuberculosis .J Antimicrob Chemother. 2017 Dec 1;72(12):3272-3276. doi: 10.1093/jac/dkx316. 10.1093/jac/dkx316