TH (tyrosine hydroxylase)
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TH is a gene that codes for the protein tyrosine hydroxylase, a key enzyme involved in the synthesis of catecholamine neurotransmitters and hormones (i.e. dopamine, norepinephrine, epinephrine). Catecholaminergic signaling is critical to regulation of sympathetic arousal (i.e. fight-or-flight response) and plays a key role in a variety of complex neural processes, including decision making, reward processing, and motor coordination.
Tyrosine hydroxylase is encoded by a single gene (TH) in all species studied, and is ubiquitous throughout the animal kingdom. Generally, the amino acid sequence encoded by TH is highly conserved. Human TH demonstrates 89%, 74%, 76%, and 50% sequence homology with rat, bovine, quail, and drosophila, respectively, in coding regions. In particular, regions encoding amino acids essential to formation of the catalytic site (i.e. C-teriminal regions) are highly homologous among mammalian species.
There are, however, key differences in this gene between humans and other mammals. While all non-primate mammals and New-World primates express a single isoform (i.e. protein resulting from a given gene) of tyrosine hydroxylase (type 1), Old-World primates express two isoforms (types 1 and 2), and humans express four (types 1, 2, 3, and 4). Additionally, humans uniquely display selective expression of these multiple TH isoforms on particular neurons, in contrast to the two isoforms possessed by Old-World primates, which invariably colocalize.
Differences in TH splicing and expression between humans, anthropoedia, and subprimates reflect evolutionarily recent increases in complexity of catecholamine biosynthesis that may provide insight into cognitive and other neurobiological differences between species.
Tyrosine hydroxylase catalyzes the conversion of tyrosine to 3,4-dihydroxyphenylalanine (DOPA), the first and rate-limiting step in the synthesis of dopamine, which can then be further modified to norepinephrine and epinephrine by other enzymes. Given its integral role in the biosynthesis of catecholamines, abnormal expression of TH has been associated with disorders such as schizophrenia, Huntington's disease, Parkinson's disease (particularly infantile PD), and various dystonias in humans
Human TH contains an additional exon relative to rodents and non-human primates, and encodes threonine rather than serine in the 8th amino acid position. Additionally, while all non-primate mammals and New-World primates express a single isoform (i.e. protein resulting from a given gene) of tyrosine hydroxylase (type 1), Old-World primates express two isoforms (types 1 and 2), and humans express four (types 1, 2, 3, and 4). Type 1 TH is highly conserved between all mammalian species, and type 2 in anthropoedia is homologous to the second isoform in humans, produced via inclusion of information encoded on the first exon. Types 3 and 4 are unique to humans, and require an alternative splicing event to include genetic information encoded in the additional exon possessed by humans. More specifically, the 5' coding regions of human TH mRNAs differ from the single-isoform variety via the insertion of 12 (type 2 TH), 81 (type 3 TH), or 12 plus 81 (type 4 TH) additional nucleotides between nucleotides 90 and 91 of type 1 TH, with the 12 additional bp encoded on the conserved first exon, and the 81 bp encoded on the human-specific exon.
These inserted amino acids (4, 27, and 31 for types 2, 3, and 4, respectively) are adjacent to a serine residue (Ser31) near the N-terminus of the resulting protein which serves as one site for phosphorylation and subsequent modulation of enzymatic activity. Due to altered protein structure around this site, kinase and phosphatase access (i.e. phosphorylating and dephosphorylating enzymes, respectively) to Ser31 differ between TH isoforms, resulting in differential activity between isoforms.
It should also be noted that while Old-World primates produce multiple isoforms of tyrosine hydroxylase, there is no evidence of selective expression or distribution of type 1 or type 2 TH in particular cell bodies or terminal fields. Rather, the two appear to colocalize, with the same relative abundance regardless of region or subcellular location. In contrast, in many human catecholaminergic neurons and axon terminals, only one TH isoform could be detected, suggesting that isoforms can be selectively expressed to differentially modulate signaling dynamics.
Humans posses a greater number of possible TH isoforms compared to any other species. While almost every species produces only one isoform of TH, Old-World primates produce two, whereas humans produce four. Humans are also the only species to display selective/differential expression of TH isoforms between neurons.
TH is expressed in all humans, and all humans possess four isoforms that can be selectively expressed.
Given differences in activity between TH isoforms, the selective expression of additional tyrosine hydroxylase isoforms may be one mechanism by which the human nervous system maintains a capacity for more complex calculation, as differential expression of tyrosine hydroxylase can permit more fine-tuned modulation of catacholaminergic signaling events.
The outstanding capacity of the human brain for complex calculation has undoubtedly contributed to our unique cognitive faculties, and may underlie many human-specific behaviors and characteristics. Differential isoform expression of TH is one mechanism by which the human brain has developed an additional level of signaling complexity relative to other species. This distinction may be one of many physiological changes that allowed the modernization of human cognition, and may thus contribute to highly complex cognitive functions such as theory of mind.
TH is expressed in virtually all animals in some form, though multiple isoforms are only present in humans and Old-World primates.
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