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Sweet-tooth Gene Discovered
Identification of the first taste receptors in humans and mice that detect sweetness.
Mouse gene found in Celera Database.

Researchers have identified the first taste receptors in humans and mice that detect sweetness. They also discovered two sequence variations within the sweet-taste gene that may explain why some mice have a 'sweet tooth' and others do not. The research is of great interest to beverage and food companies that design novel artificial sweeteners.

Two T1R3 proteins join to form a sweet-taste receptor. The red 'glob' (white arrow) is a bulky sugar molecule that modifies the sweet-taste receptor in the non-taster mice. View larger

Researchers at Mount Sinai School of Medicine in New York isolated the human sweet-taste gene, which they subsequently used to single out the mouse version from the mouse genome fragment database at Celera Genomics. The mouse gene is called Tas1r3, for taste receptor family 1, member 3.

Researchers at Harvard Medical School used the human sweet-taste gene to fish out Tas1r3 from a library of mouse genes that are active in taste-bud cells.

For the past 25 years, scientists have known that a taste for sweet foods is a trait with a genetic element, but the actual genes have been elusive. About a decade ago, progress was made as scientists determined that a region of the mouse chromosome 4 called Sac (short for saccharin) was associated with a preference for sweets.

When Robert Margolskee, of Mount Sinai School of Medicine of New York University, and colleagues began the search for the sweet-taste gene one year ago, the mouse genome project had barely begun, and very little sequence was available. The human genome sequence, by comparison, was almost complete. Margolskee used a short genetic sequence from the mouse Sac region as bait to find the equivalent region in the human genome. Linda Buck, of Harvard Medical School, in Boston, Massachusetts, and her team were also looking for the gene and took the same approach.

Both Buck and Margolskee's teams identified a region of human chromosome 1 that corresponds to the Sac region of mouse chromosome 4. Having narrowed the region to a million units of DNA containing about 23 possible genes, Margolskee examined each one and found a gene that looked like a taste receptor. Buck used other taste receptors as models to fish for similar-looking genes. Both teams identified Tas1r3.

Tas1r3 produces a receptor protein called T1R3. The T1R3 protein is anchored in the membrane of the cell with a large globular region hanging outside. It is the outer globular part of the protein that is believed to interact directly with sugar molecules.

Margolskee's team examined the T1R3 gene in taster and non-taster strains of mice to determine whether differences in gene sequence could explain the tasters' sweet tooth. There were only two differences in the gene sequence that separated all the tasters from the non-tasters: T55A and I60T.

"We are absolutely sure that we have found the genetic variations that cause the difference between the sugar-loving taster mice and the non-tasters," says Margolskee. Only the taster strains have the amino acids threonine and isoleucine at positions 55 and 60, respectively, of the T1R3 protein receptor.

The I60T change, which leads to the replacement of the amino acid isoleucine with threonine in the non-taster strain, may lead to structural modifications of the receptor, according to Margolskee and his co-authors. Their article appears in the May issue of Nature Genetics. Ironically, the altered amino acid sequence may lead to the addition of a bulky, complex sugar molecule to the T1R3 receptor and prevent the receptor from behaving normally.

Based on comparisons to other receptors, Margolskee's team believes two copies of T1R3 are needed to create a working receptor; the addition of a sugar molecule would act like a wedge and prevent the two halves of the receptor from closing.

Linda Buck and her colleagues identified the same genetic variations between the taster and the non-taster mice. Their results are published in the May issue of Nature Neuroscience.

Margolskee intends to further study the human taste receptor gene. He is interested in whether taste receptor genes could influence overindulgence in sweet foods leading to obesity.

See related GNN article
»The Fly’s Sensational Sequence

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Max, M. et al. Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac. Nat Genet 28, 58-63 (May 2001).
Montmayeur, J.-P. et al. A candidate taste receptor gene near a sweet taste locus. Nat Neurosci 4, 492-497 (May 2001).

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