Sandbox Reserved 769

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This Sandbox is Reserved from Sep 25, 2013, through Mar 31, 2014 for use in the course "BCH455/555 Proteins and Molecular Mechanisms" taught by Michael B. Goshe at the North Carolina State University. This reservation includes Sandbox Reserved 299, Sandbox Reserved 300 and Sandbox Reserved 760 through Sandbox Reserved 779.

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spinqualitylabelsall models Structure of a tryptophan synthase quinonoid intermediate. Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Tryptophan SynthaseTryptophan Synthase

Tryptophan synthase is an enzyme that catalyzes the final two steps in the biosynthesis of tryptophan. It is commonly found in Eubacteria, Archaebacteria, Protista, Fungi, and Plantae. However, it is absent from Animalia.

Tryptophan Synthase is an ideal model for illustrating the complex protein-protein interactions that occur between biomolecules. Each subunit communicates with the other cooperatively to maximize the catalytic rate of the synthesis of L-tryptophan from indole-3-glycerol-phosphate. The overall synthesis is completed by the substrate binding to the active site in the a-subunit, the product then channeled to the b-subunit active site, and then the product released.

General InformationGeneral Information

Gene Name: trpA, trpB

Organism: Salmonella typhimurium (strain LT2)

Classification: Lyase

Length: trpA: 268 AA trpB: 397 AA

Molecular Weight: 72012.45 Da

Isoelectric Point: 5.62

Chains: A, B

Ligands: Sodium Ion ([1]), pyridoxal-5'-phosphate ([2])

Enzyme StructureEnzyme Structure

Tryptophan synthase typically exists as an α-ββ-α complex. The α subunit has an α/β barrel, which is formed from eight parallel beta strands with eight parallel α-helicies packed around it.The β-subunit consists of two domains called the N-terminal domain and C-terminal domain.

Hydrophobic ChannelHydrophobic Channel

The α and β active sites are separated by a 30 Å long hydrophobic channel contained within the enzyme allowing for the diffusion of indole. If the channel did not exist, the indole formed at an α active site would quickly diffuse away and be lost to the cell as it is hydrophobic and can easily cross membranes. As such, the channel is essential for enzyme complex function

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Sequence of TrpA and Trp BSequence of TrpA and Trp B

Alpha Subunit

Beta Subunit

Enzyme MechanismEnzyme Mechanism

Indole-3-glycerol-phosphate (IGP) is cleaved by the tryptophan synthase α-subunit (TSA) to indole and glyceraldehyde-3-phosphate (GDP) This is known as the α-reaction. The alpha reaction is reversible. Then indole is transported via a 30 Å intermolecular tunnel to the tryptophan synthase β-subunits (TSB) that catalyze the condensation of indole and serine to tryptophan. This is known as the β-reaction and it is a pyridoxal-5-phosphate (PLP) dependent reaction.

The substrates and ligands that bind to the various sites of tryptophan synthase cause conformational changes not only in that particular subunit, but also in the other subunits, making the complete mechanism cooperative.

Active SitesActive Sites

α subunit reaction: The αGlu49 and αAsp60 are thought to be directly involved in the catalysis as shown.

β subunit reaction: The βLys87, βGlu109, and βSer377 are thought to be directly involved in the catalysis as shown.

Medical RelevanceMedical Relevance

As humans do not have tryptophan synthase, this enzyme has been explored as a potential drug target.

Inhibition of tryptophan synthase in amino acid metabolism has been suggested for:

• Treatment of tuberculosis

• Treatment of ocular and genital infections

• Treatment of cryptosporidiosis

• Herbicide use