Many biomolecules are in two versions, which are a mirror image of the other, such as left and right hand. Cells typically use the left-hand version of amino acids to produce proteins and it is believed that swallow mechanisms share this preference. Scientists from the University of Groningen have already shown that prokaryotic transport protein can transport both versions of the amino acid aspartate with equal efficacy. A detailed analysis of the structure of the transporter shows why this is so. The results were published in the magazine eLife on April 24.
The "practicality" of life has been known for over a century. Many organic molecules are produced in two versions that have the same chemical formula and bond between the atoms but are structurally mirror images of others. During the evolution of some molecules the left version (L) is selected while for others the mirror image (D) is used. This is a drug issue, where only one version is sometimes effective and the other version can cause serious side effects.
"Living organisms use L-amino acids in protein production, but sometimes they will use D-amino acids, for example in bacterial cell walls," explains Groningen University Professor of Biochemistry Dirk Slotob. The central nervous system of mammals has a transport protein for the neurotransmitter L-glutamate, which can also transport aspartate to the amino acid. "And that turns out to recognize L-aspartate and D-aspartate.
This is contrary to expectations. Since L-amino acids are functionally active compounds, it would make sense to transport proteins only to choose a "hand". Slotboom: "This follows from the difference in structure. Recognition by a transporter requires the structure of the molecule to fit in the binding site. And just as it is not possible for your left hand to fit in a right-handed glove, binding of D-amino acids to the transport protein that evolves to take L-amino acids is impossible.
So far, no real mechanistic or structural studies have been conducted to explain why the central nervous system conveyor does not seem to lend itself to this logic. So Slotboom, along with his colleague Albert Guskov, an assistant and head of the biomolecular X-ray crystallography laboratory, decided to deal with this issue. Their post-doctor Valentina Arhipova carried out a structural analysis of the transport protein while the doctoral students. student Gianluka Trinko performs functional research. For their experiments, they use the homologous transport protein found in microorganisms that has a binding site that is almost identical to that of the mammalian transporter.
Trinco found that L-aspartate and D-aspartate were transported in the same way, driven by the translocation of three sodium ions. "In addition, the affinity for the two substrates is similar," he says. Arhipova studies the structure of the L- or D-aspartate binding site. She noticed that D-aspartate had been accommodated only with small rearrangements of the structure: "The key is that there is room enough for the geometrically different D-aspartate to connect. The binding site is not like a glove, but rather as a glove.
For microorganisms, the protein transports only aspartate that cells can use to build proteins and also use as 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 the nerve impulse is transmitted to another neuron.
There are indications that aspartate may also act as a neurotransmitter. "If this is the case, both L- and D-aspartates can perform this function," says Slotboom. "The affinity for both types of aspartate is very high. This may indicate a function and suggests that D-aspartate is also used for something. Interestingly, D-glutamate is not accepted by the transporter. Again, this seems to be a matter of space: glutamate has an additional methylene group compared to aspartate. – A in D-glutamate methylene probably leads to a collision with the binding site. It does not fit, even in the glove.