Threonine protease

Threonine Protease
Crystal structure of human proteasome alpha 1
Identifiers
Symbol	Thr

Threnonine proteases are a family of proteolytic enzymes harbouring a threonine (Thr) residue within the active site. The prototype members of this class of enzymes are the catalytic subunits of the proteasome, however the acyltransferases convergently evolved the same active site geometry and mechanism.

Mechanism

Threonine proteases use the secondary alcohol of their N-terminal threonine as a nucleophile to perform catalysis.^[1][2] The threonine must be N-terminal since the terminal amide of the same residue acts as a general base by polarising an ordered water which deprotonates the alcohol to increase its reactivity as a nucleophile.^[3][4]

Catalysis takes place in two steps:

• Firstly the nucleophile attacks the substrate to form a covalent acyl-enzyme intermediate, releasing the first product.
• Secondly the immediate is hydrolised by water to regenerate the free enzyme and release the second product.
  • In ornithine acyltransferase, instead of water, the substrate ornithine (the acceptor) performs the second nucleophilic attack and so leaves with the acyl group.

Classification and evolution

Evolutionary convergence of threonine proteases towards the same N-terminal active site organisation. Shown are the catalytic threonine of the proteasome (clan PB, family T1) and ornithine acetyltransferase (clan PE, family T5).

Five families belonging to two separate superfamilies are currently recognised: the Ntn fold proteosomes^[1] (superfamily PB) and the DOM fold ornithine acyltransferases^[2] (superfamily PE). The two superfamilies represent two independent, convergent evolutions of the same active site.^[4][5]

Superfamily	Threonine protease families	Examples
PB clan	T1, T2, T3, T6	archaean proteasome, beta component (Thermoplasma acidophilum)
PE clan	T5	ornithine acetyltransferase (Saccharomyces cerevisiae)

See also

• Protease
  • serine-
  • cysteine-
  • aspartic-
  • metallo-
• Enzyme
• Proteolysis
• Catalytic triad
• Convergent evolution
• The Proteolysis Map
• Protease inhibitor (pharmacology)
• Protease inhibitor (biology)
• TopFIND - database of protease specificity, substrates, products and inhibitors
• MEROPS - database of protease evolutionary groups

References

1. Brannigan, JA; Dodson, G; Duggleby, HJ; Moody, PC; Smith, JL; Tomchick, DR; Murzin, AG (Nov 23, 1995). "A protein catalytic framework with an N-terminal nucleophile is capable of self-activation.". Nature 378 (6555): 416–9. doi:10.1038/378416a0. PMID 7477383.
2. Cheng, H; Grishin, NV (July 2005). "DOM-fold: a structure with crossing loops found in DmpA, ornithine acetyltransferase, and molybdenum cofactor-binding domain.". Protein science : a publication of the Protein Society 14 (7): 1902–10. doi:10.1110/ps.051364905. PMID 15937278.
3. Dodson, G; Wlodawer, A (September 1998). "Catalytic triads and their relatives.". Trends in Biochemical Sciences 23 (9): 347–52. doi:10.1016/S0968-0004(98)01254-7. PMID 9787641.
4. Ekici, OD; Paetzel, M; Dalbey, RE (December 2008). "Unconventional serine proteases: variations on the catalytic Ser/His/Asp triad configuration.". Protein science : a publication of the Protein Society 17 (12): 2023–37. doi:10.1110/ps.035436.108. PMID 18824507.
5. Buller, AR; Townsend, CA (Feb 19, 2013). "Intrinsic evolutionary constraints on protease structure, enzyme acylation, and the identity of the catalytic triad.". Proceedings of the National Academy of Sciences of the United States of America 110 (8): E653–61. doi:10.1073/pnas.1221050110. PMID 23382230.