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Literature summary extracted from

  • Hofto, L.R.; Lee, C.E.; Cafiero, M.
    The importance of aromatic-type interactions in serotonin synthesis: Protein-ligand interactionsin tryptophan hydroxylase and aromatic amino acid decarboxylase (2008), J. Comput. Chem., 30, 1111-1115.
    View publication on PubMed

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
1.14.16.4 residue Phe241 forms a displaced sandwich-type pi-complex with tetrahydrobiopterin, this complex has a counterpoise-corrected second order Moller Plesset Theory interaction energy of about 24.68 kcal/mol synthetic construct

Protein Variants

EC Number Protein Variants Comment Organism
1.14.16.4 F241A drop in interaction energy of 58% synthetic construct
1.14.16.4 F241G loses 76% of the interaction energy synthetic construct
1.14.16.4 F241I drop in interaction energy of 4%, reduction in interaction for the isoleucine mutation may cause a reduction in the production of 5-hydroxy-L-tryptophan, and in turn, a reduction in serotonin. This may lead to onset of symptoms, such as anxiety, depression, and OCD synthetic construct
1.14.16.4 F241L retains the interaction energy necessary to keep protein function synthetic construct
1.14.16.4 F241Q retains the interaction energy necessary to keep protein function synthetic construct
1.14.16.4 F241Y retains the interaction energy necessary to keep protein function synthetic construct
4.1.1.28 additional information Model chemistry by second-order Moller-Plessett perturbation theory calculations, phenylalanine in position 103 is replaced by all native amino acids. The mutant residues which conserve an aromatic side chain (tyrosine and tryptophan) retain near 100% interaction energy with the carbidopa, and thus most likely retain full protein function. Arginine has an interaction energy of 555% of the wild-type. This is due to the fact that the long, polar side chain is able to find a geometry where a hydrogen bond is being made with the hydroxyl group of the carbidopa. The small side chains are not close enough to the carbidopa to have a large deal of dispersion/induction interactions. Residues are arranged by the size of the side chain, and with a few exception, the interaction energy generally increases with size of the side chain. Glycine, alanine, serine, threonine, and histidine all fall below the above mentioned 20% threshold and would likely cause a loss of protein function. Serine contains a polar side chain and histidine has pi-electrons, yet these residues are too small and too far removed to have strong interactions. Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
4.1.1.28 5-Hydroxytryptophan Homo sapiens The biosynthesis of serotonin requires aromatic substrates to be bound in the active sites of the enzymes tryptophan hydroxylase and aromatic amino acid decarboxylase Serotonin + CO2
-
 ?
4.1.1.28 L-Dopa Homo sapiens
-
 dopamine + CO2
-
 ?
4.1.1.28 additional information Homo sapiens Mutations that decrease substrate binding can result in a decrease in serotonin production and thus can lead to depression and related disorders ?
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.14.16.4 synthetic construct
-
-
-
4.1.1.28 Homo sapiens
-
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.14.16.4 L-tryptophan + tetrahydrobiopterin + O2
-
 synthetic construct 5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
 ?
4.1.1.28 5-Hydroxytryptophan The biosynthesis of serotonin requires aromatic substrates to be bound in the active sites of the enzymes tryptophan hydroxylase and aromatic amino acid decarboxylase Homo sapiens Serotonin + CO2
-
 ?
4.1.1.28 carbidopa interaction of carbidopa with the Phe103 residue of the enzyme, the residue forms a displaced sandwich-type sigma-complex with carbidopa Homo sapiens ?
-
 ?
4.1.1.28 L-Dopa
-
 Homo sapiens dopamine + CO2
-
 ?
4.1.1.28 additional information Mutations that decrease substrate binding can result in a decrease in serotonin production and thus can lead to depression and related disorders Homo sapiens ?
-
 ?

Synonyms

EC Number Synonyms Comment Organism
1.14.16.4 TRpOH
-
 synthetic construct
1.14.16.4 tryptophan hydroxylase
-
 synthetic construct
4.1.1.28 AACD
-
 Homo sapiens
4.1.1.28 Aromatic amino acid decarboxylase
-
 Homo sapiens

Cofactor

EC Number Cofactor Comment Organism Structure
1.14.16.4 tetrahydrobiopterin
-
 synthetic construct