Molecule Information

General Information of the Molecule (ID: Mol02002)

• Name: Alanine racemase (ALR) ,Mycobacterium tuberculosis
• Synonyms: alr; Rv3423c; MTCY78.06
• Molecule Type: Protein
• Gene Name: ALR
• Gene ID: 887634
• Sequence:
  MAMTPISQTPGLLAEAMVDLGAIEHNVRVLREHAGHAQLMAVVKADGYGHGATRVAQTAL
  GAGAAELGVATVDEALALRADGITAPVLAWLHPPGIDFGPALLADVQVAVSSLRQLDELL
  HAVRRTGRTATVTVKVDTGLNRNGVGPAQFPAMLTALRQAMAEDAVRLRGLMSHMVYADK
  PDDSINDVQAQRFTAFLAQAREQGVRFEVAHLSNSSATMARPDLTFDLVRPGIAVYGLSP
  VPALGDMGLVPAMTVKCAVALVKSIRAGEGVSYGHTWIAPRDTNLALLPIGYADGVFRSL
  GGRLEVLINGRRCPGVGRICMDQFMVDLGPGPLDVAEGDEAILFGPGIRGEPTAQDWADL
  VGTIHYEVVTSPRGRITRTYREAENR
• Function: Catalyzes the interconversion of L-alanine and D-alanine. D-alanine plays a key role in peptidoglycan cross-linking.
• Uniprot ID: ALR_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 [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.

Disease Class: Tuberculosis [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Cycloserine
• Molecule Alteration: Missense mutation; p.C1030T
• 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