A new gain-of-function allele in chimpanzee tryptophan hydroxylase 2 and the comparison of its enzyme activity with that in humans and rats.
Tryptophan hydroxylase 2 (TPH2) is a rate-limiting enzyme of neuronal serotonin biosynthesis. Recently, two single nucleotide polymorphisms (SNPs) at the exon 11 coding region that resulted in amino acid substitutions in the C-terminal domain have been reported to affect enzyme activity in humans and mice. We determined 175 base-pair sequences of the exon 11 region in nine primate species from all recognized lineages. All nucleotide sequence substitutions were synonymous, with the exception of one adenine (A) to guanine (G) substitution at the 1404th position in the open reading frame (ORF). This substitution leads to a glutamine (Q) to arginine (R) amino acid substitution at the 468th position within chimpanzee sequences. The frequency of the G allele was 0.24 among 66 chimpanzees. Therefore, it is a novel SNP observed in chimpanzees, and we have named these two alleles as ch468Q and ch468R, respectively. When expressed in HeLa cells, ch468R caused an approximate 20% increase in enzyme function during L-5-hydroxytryptophan (5HTP) production (P<0.001). We also surveyed the interspecies difference in enzyme activity among human, chimpanzee, and rat. Although the rat showed an identical amino acid sequence at the C-terminal region as those of human and ch468Q, the rat enzyme was more active than those of human or chimpanzee (P<0.001), indicating the importance of substitutions in other regions. Our findings on the chimpanzee SNP will be a useful genetic marker in understanding the individual difference in the serotonin-related behavior.
Hong
Kyung-Won
KW
The United Graduate School of Agricultural Science, Gifu University, Gifu 501-1193, Japan.
Sugawara
Yuko
Y
Hasegawa
Hiroyuki
H
Hayasaka
Ikuo
I
Hashimoto
Ryota
R
Ito
Shin'ichi
S
Inoue-Murayama
Miho
M
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine / Q000235:genetics; D001483:Base Sequence; D005787:Gene Frequency; D018698:Glutamic Acid / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D051381:Rats; D014365:Tryptophan Hydroxylase / Q000235:genetics* / Q000378:metabolism
D018698:Glutamic Acid; D001120:Arginine; D006916:5-Hydroxytryptophan; D014365:Tryptophan Hydroxylase