Tryptophan hydroxylase, properties

The synthesis of 5-HT can increase markedly under conditions requiring more neurotransmitter. Plasticity is an important concept in neurobiology. In general, this refers to the ability of neuronal systems to conform to either short- or long-term demands placed upon their activity or function (see Plasticity in Ch. 53). One of the processes contributing to neuronal plasticity is the ability to increase the rate of neurotransmitter synthesis and release in response to increased neuronal activity. Serotonergic neurons have this capability the synthesis of 5-HT from tryptophan is increased in a frequency-dependent manner in response to electrical stimulation of serotonergic soma [7]. The increase in synthesis results from the enhanced conversion of tryptophan to 5-HTP and is dependent on extracellular calcium ion. It is likely that the increased 5-HT synthesis results in part from alterations in the kinetic properties of tryptophan hydroxylase, perhaps due to calcium-dependent phosphorylation of the enzyme by calmodulin-dependent protein kinase II or cAMP-dependent protein kinase (PKA see Ch. 23). 

Short-term requirements for increases in the synthesis of 5-HT can be met by post-translational processes, such as phosphorylation, that change the kinetic properties of tryptophan hydroxylase without necessitating the synthesis of more molecules of tryptophan hydroxylase. By contrast, situations requiring long-term increases in the synthesis and release of 5-HT result in the synthesis of tryptophan hydroxylase protein. For example, partial but substantial destruction (>60%) of central serotonergic neurons results in an increase in the synthesis of 5-HT in... 

The following is review on the molecular and physical properties of this class of monooxygenases, which are also known as hydroxylases. A typical monooxygenase reaction is the hydroxylation of an alkane to an alcohol which involves a reduced cosubstrate that reduces a second atom within the O2 molecule to form water. Flavin-containing monooxygenases include lysine oxygenase and 4-hydroxybenzoate hydroxylase. Reduced pteri-dines are involved in the phenylalanine hydroxylase and tryptophan hydroxylase reactions. See also Cytochrome P-450... 

NSC 77370 CP 10188) is an ENZYME INHIBITOR, a selective irreversible tryptophan hydroxylase inhibitor, thereby depleting 5-HT in the brain. As an indirect 5-HT antagonist, it has been given to patients with carcinoid syndrome to relieve some of the symptoms, fendiline [inn] is a methylbenzylamine, a CALCIUM-CHANNEL BLOCKER and calmodulin antagonist, with coronary VASODILATOR properties. 

Strain differences in the activity of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, have been reported in rats22-23 and in mice.24 Chaouloff et al.22 reported that the activity of tryptophan hydroxylase was decreased in Lewis rats compared with Fisher 344 rats. Kulikov et al.23 reported that in vitro central tryptophan hydroxylase activity was higher in the Lewis strain of rats than in spontaneously hypertensive rats. In mice, Knapp and Mandell24 reported that midbrain tryptophan hydroxylase from two behaviorally different mouse strains, C57B1/6J and A/J, had different stabilities and regulatory properties. 

Knapp, S. and Mandell, A. J., Mouse midbrain tryptophan hydroxylase Strain differences in variational properties, /. Physiol., 77, 281, 1981. 

The tetrahydrobiopterin formed in fhis reaction is similar in structure to a reduced flavin. The mechanism of its interaction with O2 could reasonably be the same as that of 4-hydroxybenzoafe hydroxylase. However, phenylalanine hydroxylase, which cafalyzes the formation of tyrosine (Eq. 18-45), a dimer of 451-residue subunits, contains one Fe per subuniO whereas flavin monooxygenases are devoid of iron, lyrosine hydroxylase and tryptophan hydroxylase have very similar properties. All three enzymes contain regulatory, catalytic, and tetramerization domains as well as a common Fe-binding motif in their active... 

Toloxatone (94) antagonized reserpine and potentiated the effects of trypt-amine and 5-HTP but not of DOPA. It had no amphetamine like, anticholiner c, antihistaminic or MAO inhibiting properties [251-253]. A later study showed that the compound was characterized by two agonistic effects activation of tryptophan hydroxylase (in vitro) and an inhibition of MAO activity in the rat brain stem, with 5>HT used as a substrate. A possible interaction in the catecholamine pathways was not excluded [254]. 

---