Cofactors

Pyridoxal 5'-phosphate.

Reaction Mechanism

threonine synthase By Reference

Threonine synthase (TS) from Saccharomyces cerevisiae catalyses the conversion of O-phospho-L-homoserine (OPHS) into threonine and phosphate. This is the final step in threonine biosynthesis. The enzyme requires a pyridoxal 5'-phosphate (PLP) cofactor which binds at the interface of all three of the protein's domains.




• Summary
• Step 1
• Step 2
• Step 3
• Step 4
• Step 5
• Step 6
• Step 7
• Step 8
• Step 9
• Step 10
• Products

The catalytic cycle starts with a transaldimination reaction. Lys124 which is initially bound to the PLP cofactor is replaced by OPHS forming the external aldimine. Lys124 catalyses the abstraction of the C-alpha proton of the substrate and its transfer to the PLP C4' position. Next, Lys124 stereospecifically abstracts the beta-pro-S hydrogen leading to the non-hydrolytic elimination of the gamma-phosphate. The gamma-methylene group left after the elimination is reprotonated producing the PLP-derivative of E-aminocrotonate. Next, water is added at C-beta. Finally, reverse transaldimination yields L-threonine.

Catalytic Residues

AA	Uniprot	Uniprot Resid	PDB	PDB Resid
Lys	P16120	124	1kl7	124

Step Components

overall reactant used, proton transfer, overall product formed, intramolecular elimination, bimolecular nucleophilic addition, assisted tautomerisation (not keto-enol), native state of cofactor regenerated, intermediate formation, schiff base formed, intermediate terminated, native state of enzyme regenerated, cofactor used, proton relay, intermediate collapse



Step 1.

The amino group of the serine performs a nucleophilic attack on the imine carbon of the lys-bound PLP forming a tetrahedral intermediate.



Step 2.

Lys124 is cleaved from PLP leaving the substrate bound.



Step 3.

Lys124 abstracts a proton from the alpha carbon of the substrate causing tautomerization of the imine.



Step 4.

Lys124 abstracts a proton from the beta carbon causing a second tautomerization from imine to enamine.



Step 5.

Phosphate is eliminated from the homoserine and another imine is formed.



Step 6.

Lys124 acts as a proton relay causing another tautomerization reaction to occur.



Step 7.

Water performs a nucleophilic attack on the C=C bond of the substrate, forming a carboanion. The water is activated by Lys124.



Step 8.

The carboanion abstracts a proton from Lys124.



Step 9.

The amino group of Lys124 performs a nucleophilic attack on the imine carbon of the thr-bound PLP forming a tetrahedral intermediate.



Step 10.

Threonine is cleaved from PLP leaving Lys124 bound.



Products.

The products of the reaction.

View Reaction Mechanisms in M-CSA

Reaction Parameters

There are no kinetic parameters information for this Enzyme

Associated Proteins

Citations

• A mutation in THREONINE SYNTHASE 1 uncouples proliferation and transition domains of the root apical meristem: experimental evidence and in silico proposed mechanism.
• Modeling and simulation study to identify threonine synthase as possible drug target in Leishmania major.
• Reaction of threonine synthase with the substrate analogue 2-amino-5-phosphonopentanoate: implications into the proton transfer at the active site.
• Threonine synthase CoTHR4 is involved in infection-related morphogenesis during the pre-penetration stage in Colletotrichum orbiculare.
• Threonine synthase CoTHR4 is involved in infection-related morphogenesis during the pre-penetration stage in Colletotrichum orbiculare
• Molecular Mechanism of the Reaction Specificity in Threonine Synthase: Importance of the Substrate Conformations.
• Evolutionary analysis of a novel zinc ribbon in the N-terminal region of threonine synthase.
• Synthesis and biological evaluation of potential threonine synthase inhibitors: Rhizocticin A and Plumbemycin A.
• Assessment of the anti-inflammatory mechanism of quercetin 3,7-dirhamnoside using an integrated pharmacology strategy.
• A QM/MM study of the L-threonine formation reaction of threonine synthase: implications into the mechanism of the reaction specificity.
• New insights into glycogen synthase kinase-3: A common target for neurodegenerative diseases.