Antigen 85
The Antigen 85 Complex (composed of protein isoforms Ag85A, Ag85B, and Ag85C) is a group of enzymatic proteins found in the Mycobacterium genus, which plays roles in pathogenic immunogenicity and cell wall synthesis. The Antigen 85 Complex (Ag85) is a mycolyltransferase, acting as the final step in the mycolic acid assembly pathway, linking the newly formed mycolic acids to the arabinogalactan layer of the cell wall. Ag85 also plays a role in virulence, utilizing its fibronectin-binding protein activities to attach to host mucosal membranes in the respiratory tract. While no approved drugs exist, substances like Ebselen and Selamectin have shown promising results in silico. Its immunogenic aspect also makes this antigen highly favored in vaccine composition for Mycobacterium tuberculosis.
Protein and natural substrate¶
Ag85 catalyzes two molecules of trehalose monomycolate to create trehalose dimycolate (TDM) and a free trehalose molecule, using the TDM to create the outer mycomembrane, which prevents phagolysosomal fusion within the host macrophage. Ag85 also catalyzes a molecule of trehalose monomycolate to a molecule of arabinogalactan to create mycolyl-arabinogalactan, and a molecule of free trehalose.
Available crystal structures¶
There are many available crystal structures of the three Antigen 85 Isoforms. A brief selection is summarized below.
Table 1 - Antigen 85C
| pdb | year | resolution | notes |
|---|---|---|---|
| 1DQZ | 2000 | 1.50 | Dimer |
| 1DQY | 2000 | 1.83 | Co-crystal with diethyl phosphate |
| 4MQL | 2013 | 1.30 | Mutation at AA #211 |
| 4QEK | 2014 | 1.30 | Mutation at AA #125 |
| 4QE3 | 2014 | 1.35 | Mutation at AA #265 |
| 4QDU | 2014 | 1.40 | Co-crystal with Ebselen |
| 4QDX | 2014 | 1.50 | Mutation at AA #210 |
| 4QDT | 2014 | 1.50 | Co-crystal with Iodoacetamide |
| 4QDZ | 2014 | 1.89 | Mutation at AA #230 |
| 4QDO | 2014 | 1.90 | Co-crystal with p-chloromercuribenzoic acid |
| 1VA5 | 2004 | 2.02 | Co-crystal with octylthioglucoside |
Table 2 - Antigen 85B
| pdb | year | resolution | notes |
|---|---|---|---|
| 1F0N | 2000 | 1.80 | Apo |
| 1F0P | 2000 | 1.90 | Co-crystal with Trehalose (natural substrate) |
Table 3 - Antigen 85A
| pdb | year | resolution | notes |
|---|---|---|---|
| 1SFR | 2004 | 2.70 | Apo |
Inhibitors¶
No approved inhibitor, but many inhibitors being studied pre-clinically and have proven to effectively inhibit the enzyme. These include Ebselen, Iodoacetamide, P-chloromercuribenzoic acid, and Portentol, Aspicilin, Parietinic acid, and Polyporic acid have been used in silico. Research on Antigen 85 has been primarily geared toward the creation of a mTB vaccine due to its necessity in mTB survival, as well as its abundance in the extracellular environment.
Most potential inhibitors target the Cysteine 209 or Serine 124, which have proved to mitigate the enzyme and prevent enzymatic metabolism.
Equilibrated Computational Structures¶
Citations¶
1: Wiker HG, Harboe M. The antigen 85 complex: a major secretion product of Mycobacterium tuberculosis. Microbiol Rev. 1992 Dec;56(4):648-61.
2: Bentley-Hibbert SI, Quan X, Newman T, Huygen K, Godfrey HP. Pathophysiology of antigen 85 in patients with active tuberculosis: antigen 85 circulates as complexes with fibronectin and immunoglobulin G. Infect Immun. 1999 Feb;67(2):581-8.
3: Ronning, D., Klabunde, T., Besra, G. et al. Crystal structure of the secreted form of antigen 85C reveals potential targets for mycobacterial drugs and vaccines. Nat Struct Mol Biol 7, 141–146 (2000).