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Sweetness and sweeteners - Competitive and allosteric modulators of sweetness

Q: What happens when lactisole wants to inhibit the sweet response of acesulfame K ?

Lactisole: binding site III Acesulfame K : binding site I or II EC50 no difference --> affinity of acesulfame K to the receptor is unaffected, Fluorescent response decreases --> less VFTD of the receptor available to actively bind acesulfame K Lactisole is an allosteric inhibitor for acesulfame K. They have different, non-overlapping, binding sites on the receptor. The inhibitor affects the binding of the actual tastant, probably by modifying the receptors conformation, without affecting binding affinity of the actual ligand.

5 important questions on Sweetness and sweeteners - Competitive and allosteric modulators of sweetness

Which compounds bind at binding site III?

Synergistic sweeteners (i.e. Cyclamate and NHDC), and sweet blocker lactisole

Where does cyclamate dock and how does it differ from lactisole?

Cyclamate docks higher in the transmembrane domain than lactisole, provoking a different conformation of the T1R2/T1R3 heterodimer allowing for increased Ca2+ influx into the cells rather than locking the receptor pair in the inactive ground state.

What happens when lactisole wants to inhibit the sweet response of cyclamate?

Both in binding site III. Lactisole inhibits binding of cyclamate to the transmembrane domain competitively. They compete for the same position in the binding pocket

The EC50 value of cyclamate increases (sigmoid curve to the right)
Maximum fluorescent response is not affected

What happens when lactisole wants to inhibit the sweet response of acesulfame K?

Lactisole: binding site III
Acesulfame K: binding site I or II

EC50 no difference --> affinity of acesulfame K to the receptor is unaffected,

Fluorescent response decreases --> less VFTD of the receptor available to actively bind acesulfame K

Lactisole is an allosteric inhibitor for acesulfame K. They have different, non-overlapping, binding sites on the receptor. The inhibitor affects the binding of the actual tastant, probably by modifying the receptors conformation, without affecting binding affinity of the actual ligand.

What happens when lactisole wants to inhibit the sweet response of aspartame?

EC50 value increases --> aspartame has lower affinity for the receptor
Fluorescent response decreases --> lower maximum binding ability to the receptor

Negative cooperativity --> different molecules can bind the receptor on similar sites and on different ones --> mixed behaviour between competitive (EC50 higher) and allosteric (fluorescent lower)

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