User:EFraz14/sandbox

Tryptophan hydroxylase

Tryptophan hydroxylase (TPH) is an enzyme belonging to the aromatic amino acid hydroxylase family. This enzyme is known to catalyze the first step in the formation of serotonin. The first step is also known as the rate limiting step for the synthesis of serotonin –which is an important hormone as well as a neurotransmitter. There have been reports that mutation in the tryptophan hydroxylase enzyme coding gene has led to an increase in various disorders such as: schizophrenia, somatic anxiety, anger-related traits, bipolar disorder, suicidal behavior, addictions among other traits.

TPH has two isoforms- TPH1 and TPH2. TPH1 can be located in the pineal gland and in the gut, whereas, TPH2 is expressed primarily in the brain. Sakowski et al. performed some studies in mice to differentiate between the two isoforms. From their studies they have concluded that there is no overlapping between the two isoforms and TPH1 is the predominant form expressed in the pineal gland and in the mastocytoma cells. TPH1 has a molecular weight of 51 kDa. TPH2, on the other hand, is the predominant form of enzyme expressed in the brain cells in the following regions: mesencephalic tegmetum, stiatum and hippocampus; also, TPH2 has a molecular weight of 56 kDa (slightly more than TPH1 isoform) (Sakowski et al., 2006).

TPH1 enzyme is composed of 444 amino acids and these amino acids are highly preserved for both, TPH1 and TPH2, isoforms. TPH2, however, has a total of 485 amino acids, 41 additional amino acids at the N-terminal sequence when compared to TPH1 (Hasegawa et al., 2010). Both the enzymes are composed of three major domains consisting of: a C-terminal tetramerization sequence, central catalytic body and an N-terminal regulatory peptide. In addition to this, both enzymes are soluble and behave like a tetramer. (Ramya)

Tryptophan hydroxylase produces  5-hydroxytryptamine (Serotonin) using BH4 and O2 as co-substrates and ferrous iron as a cofactor. TPH hydroxylates tryptophan to 5-hydroxytryptophan which is then decarboxylated by the amino acid decarboxylase(need citation). The genes of the TPH isomers have a 71% homology in protein sequence. But are located on different chromosomes, TPH 1 is located on chromosome 11 and TPH2 is located on chromosome 12. A major difference between the two is that TPH1  is less stable than TPH2 and rapidly aggregates whether it is isolated or expressed, particularly without the presence of a fusion partner. In studies conducted by McKinney et al., they found that human TPH2 has a much larger N-terminal domain compared to TPH1. And that TPH2 has a lower affinity of Tryptophan, this was thought to be the cause of a more selective active cite cleft, resulting in decreased catalytic activity. The availability of Trp in living organisms (mainly mammals) has a direct effect on production rates of serotonin in the body. This limited availability could also be a reason for low affinity for Trp. (Eriel)

Tryptophan hydroxylase 2 (TPH2) is the key and rate-limiting enzyme in 5-HT synthesis in the brain. 5-HT synthesis is the conversion of tryptophan to 5-HTP by amino acid decarboxylase, the enzyme that also concert L-DOPA to dopamine. Seasonal affective disorder (SAD) is a type of depression that is related to changes in seasons. SAD begins and ends at about the same times every year. Less often, SAD causes depression in the spring or early summer. Numerous pieces of evidence indicate the association of SAD with decreased brain neurotransmitter serotonin (5-HT) system functioning. Tryptophan is an essential amino acid, and the depletion could affect general protein synthesis which could possibly lead to depression. The lack of 5-HT in at least some depressed individuals, perhaps most convincingly when suicidality or aggression is present. 5-HT deficiency could possibly arise from multiple different defects in one or more of the various components of the 5-HT system. The multiple distinct mutations in TPH2 may be a representation of such a concept.(Cassandra)

Resources

https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=7166#phenotypes

https://www.ncbi.nlm.nih.gov/pubmed/16581041 (Sakowski et al., 2006)

https://www.sciencedirect.com/topics/neuroscience/tryptophan-hydroxylase

https://www.ncbi.nlm.nih.gov/pubmed/26167977

http://www.jneurosci.org/content/jneuro/26/2/530.full.pdf

McKinney, Jeffrey, et al. “Different Properties of the Central and Peripheral Forms of Human Tryptophan Hydroxylase.” Journal of Neurochemistry, Wiley/Blackwell (10.1111), 29 Nov. 2004, onlinelibrary.wiley.com/doi/epdf/10.1111/j.1471-4159.2004.02850.x.

Jacobsen, J. P., Medvedev, I. O., & Caron, M. G. (2012). The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse. ''Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 367''(1601), 2444-59.