Protein Variants | Comment | Organism |
---|---|---|
M319T | the M319T mutation is positioned close enough to allow interaction with the D-cycloserine moiety, which, given the large change of the character of the side chain, can strongly affect D-cycloserine reactivity. M319 is located near Y364 and, as a result, it is possible that the M319T mutation alters the interaction with Y364, thereby affecting D-cycloserine inhibition. The M319T mutant enzyme shows minimal inhibition by D-cycloserine, even at 1 mM, the IC50 of this mutant cannot be determined | Mycobacterium tuberculosis |
R373L | the mutation is not directly located within the active site but near the dimer interface and close to residues M319 and D320, which play an important role in the makeup of the active site. The replacement of arginine with the short and hydrophobic side chain of leucine might disrupt molecular interactions at the dimer interface as well as destabilize the DCS binding site. The R373L mutation is not located directly within the active site, but also showa a significant increase in resistance to D-cycloserine, with an 27fold increased IC50 compared to the wild-type enzyme | Mycobacterium tuberculosis |
Y364D | the mutation to aspartic acid introduces a shorter and negatively charged side chain, which potentially affects pyridoxal 5'-phosphate orientation in the active site. The IC50 of the Y364D mutant for D-cycloserine shows a 50fold increase compared to the wild-type | Mycobacterium tuberculosis |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
D-cycloserine | DCS, inhibits enzyme Alr irreversibly by covalently bonding to pyridoxal 5'-phosphate, molecular modeling | Mycobacterium tuberculosis |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
L-alanine | Mycobacterium tuberculosis | - |
D-alanine | - |
r |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Mycobacterium tuberculosis | - |
- |
- |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
L-alanine | - |
Mycobacterium tuberculosis | D-alanine | - |
r |
Subunits | Comment | Organism |
---|---|---|
homodimer | - |
Mycobacterium tuberculosis |
Synonyms | Comment | Organism |
---|---|---|
AlrMtb | - |
Mycobacterium tuberculosis |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
pyridoxal 5'-phosphate | - |
Mycobacterium tuberculosis |
IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
---|---|---|---|---|---|
0.0264 | - |
wild-type enzyme, pH and temperature not specified in the publication | Mycobacterium tuberculosis | D-cycloserine | |
0.712 | - |
enzyme mutant R373L, pH and temperature not specified in the publication | Mycobacterium tuberculosis | D-cycloserine | |
1.328 | - |
enzyme mutant Y364D, pH and temperature not specified in the publication | Mycobacterium tuberculosis | D-cycloserine |
General Information | Comment | Organism |
---|---|---|
malfunction | role of alanine racemase mutations in Mycobacterium tuberculosis D-cycloserine resistance, overview | Mycobacterium tuberculosis |
additional information | amino acid residues 319 and 364 are located directly in the active site. Y364 is involved in the positioning of the phosphate moiety of PLP and thus represents a prominent active site residue in the conserved inner layer of the substrate entrance corridor of Alr | Mycobacterium tuberculosis |