Putting the right hand in a left-handed mitt

Many biomolecules exist in two versions that are the reverse image of the other, such as a left hand and a right hand. Cells generally use the left-handed version of amino acids to produce proteins, and capture mechanisms would share this preference. Scientists from the University of Groningen have now shown that a prokaryotic transport protein can transport both versions of the amino acid aspartate with equivalent efficacy. A detailed badysis of the carrier's structure shows why this is the case. The results were published in the journal eLife April 24.

The "character" of life has been known for more than a century. Many organic molecules are produced in two versions that have the same chemical formula and the same connectivity between the atoms but are structurally the mirror image of the other. During evolution, the left – handed version (L) was selected for some molecules, while for others, the mirror image (D) is used. This is a problem in the manufacture of drugs, where sometimes only one version is effective and the other version can cause serious side effects.

Against expectations

"Living organisms use L-amino acids in protein production, but they sometimes use D-amino acids, for example in the walls of bacterial cells," says Dirk Slotboom, professor of biochemistry at the University of Groningen. The mammalian central nervous system possesses a transport protein for the neurotransmitter L-glutamate that can also carry the amino acid aspartate. "And that turns out to recognize both L-aspartate and D-aspartate."

This goes against expectations. Since L-amino acids are functionally active compounds, it would be logical for transport proteins to select only one "hand". Slotboom: "This stems from the difference in structure recognition by a carrier requires that the structure of the molecule adapts to the binding site." And just as it is not possible to adjust your left hand in a right handed glove, the binding of D-amino acids to a transport protein that has evolved to accept L-amino acids is impossible.

Affinity

No real structural or structural study has been done to date to explain why the central nervous system transporter seems to challenge this logic. That's why Slotboom, along with his colleague Albert Guskov, badistant professor and head of the biomolecular X-ray crystallography lab, decided to tackle this issue. Their postdoctoral researcher Valentina Arkhipova conducted a structural badysis of the transport protein, while her Ph.D. student Gianluca Trinco carried out functional studies. For their experiments, they used the homologous transport protein found in microorganisms, which has a binding site almost identical to that of the mammalian transporter.

Trinco discovered that L-aspartate and D-aspartate were transported in the same way, fed by the translocation of three sodium ions. "In addition, the affinity for both substrates is similar," he says. Arkhipova studied the structure of the binding site with L-aspartate or D-aspartate. She observed that D-aspartate was suitable for minor reorganizations of the structure: "It is essential to leave enough space for the geometrically different D-aspartate to bind." The binding site does not look like a glove, but with a mitten. "

neurotransmitter

In microorganisms, the protein only carries aspartate, which cells could use to build protein and also as a fuel or as a source of nitrogen. In mammals, the homologous protein transports glutamate into the central nervous system, where the amino acid is used as a neurotransmitter. The transport protein removes L-glutamate from the synaptic cleft, the part where a nerve impulse is transmitted to another neuron.

There are indications that aspartate can also act as a neurotransmitter. "If that was the case, the L and the D-aspartate could fulfill this function," says Slotboom. "The affinity for both types of aspartate is very high.This may indicate a specific function and suggests that D-aspartate is also used for something." Interestingly, the carrier does not accept D-glutamate. Again, this seems to be a matter of space: glutamate has an additional methylene group compared to aspartate. "And in D-glutamate, this methylene probably causes a conflict with the binding site." That's wrong, not even in a mittens.