A single human gene encoding multiple tyrosine hydroxylases with different predicted functional characteristics

Abstract

Catecholaminergic systems in discrete regions of the brain are thought to be important in affective psychoses, learning and memory, reinforcement and sleep-wake cycle regulation. Tyrosine hydroxylase (TH) is the first enzyme in the pathway of catecholamine synthesis. Its importance is reflected in the diversity of the mechanisms that have been described which control its activity; TH levels vary both during development and as a function of the activity of the nervous system. Recently, we deduced the complete amino-acid sequence of rat TH from a complementary DNA clone encoding a functional enzyme. Here we demonstrate that, in man, TH molecules are encoded by at least three distinct messenger RNAs. The expression of these mRNAs varies in different parts of the nervous system. The sequence differences observed are confined to the 5' termini of the messengers and involve alternative splicing events. This variation has clear functional consequences for each putative form of the enzyme and could represent a novel means of regulating catecholamine levels in normal and pathological neurons.

Regulation of recombinant human tyrosine hydroxylase isozymes by catecholamine binding and phosphorylation

“…mg catalytic subunit-' and K, of about 5 pM enzyme subunit for both isozymes. In contrast, K, for phosphorylation of isolated bovine TH (which has a predicted amino acid sequence identical to that of the human enzymes at residues 36 -42 [7,26,271) was found to be approximately 150 pM (data not shown).…”

Nucleotide sequence of the Drosophila glucose-6-phosphate dehydrogenase gene and comparison with the homologous human gene

“…Recent studies on the messenger RNAs which encode human tyrosine hydroxylase reveal that, in man, tyrosine hydroxylase is encoded by three distinct messenger RNAs. Like the human G6PD sequences, these mRNAs and the proteins they encode are identical in their central and 3' regions but diverge at their 5' ends (Grima et al, 1987). Apparently, the heterogeneity at the 5' end results from alternative splicing events within the primary transcript.…”

Mutations in human monoamine-related neurotransmitter pathway genes

“…b ForTH, there are four splicing variants in intron 1 resulting in combinations ofTH-1 with 497 aa (exon 1 with 30 aa),TH-2 with 501 aa (extended exon 1 with 34 aa),TH-3 with 524 aa (exon 1 with 30 aa and exon 2 with 27 aa), andTH-4 with 528 aa (extended exon 1 with 34 aa and exon 2 with 27 aa; for details see Grima et al [1987] and Kaneda et al [1987]). Note that mutations in SupplementaryTable S1 are based onTH-4 with 14 exons and a total of 528 aa, and in parentheses onTH-1 with 13 exons and a total of 497 aa.…”