The structure of one of the last “transporter” machines has finally been cracked and reported in Nature. Although many questions remain, it appears to act as a rocking turnstile activated by a flow of cations (positive ions). This transporter, called NorM, a member of the MATE family (multidrug and toxic compound extrusion), exists in all domains of life, from simple bacteria to humans. Cellular export of toxins and substrates is a fundamental life process. Its importance is profound: in plants, it determines crop yields according to its ability to pump toxins out from the soil. In the liver of animals, as well as in microbes, it pumps toxins out of the body. It does such a good job that, unfortunately, it confers multi-drug resistance on some germs we would like to destroy by allowing them to pump out the medicine, or prevents targeted medicines from reaching good cells doctors would like to help. Understanding this transporter gateway enzyme is therefore of crucial importance. The team’s findings, using X-ray crystallography, show NorM to be made up of 12 intermembrane helices of amino acids, arranged in two groups of six to form a cup-shaped V pattern facing outward. When a sodium ion (Na+ enters the cup, it binds to a particular site that has “three evolutionarily conserved amino-acid side chains that can carry a negative charge due to the presence of a carboxylic acid group.” Somehow, this binding causes the cup to flip into an inward-facing conformation just long enough for the toxin inside the cell to bind to the cup. When the sodium ion is released, the cup flips back out, tossing the toxin outside the cell. This automated turnstile can pump anywhere from 14 to 1,500 molecules out per minute. Try to imagine this little cup flipping over up to 25 times per second, each time shuttling out its unwanted cargo. Even that, though, is slow compared to some other specialized transporter families that can pump 100,000 ions per minute, he said. The difference is that NorM and other MATE transporters have to shuttle a wide variety of larger molecules. The sodium ion gradient indicates that this little machine, what’s more, runs on an electrical current. A number of questions still remain about how NorM achieves its mechanical effectiveness. “Over the past decade, crystallographic evidence has been obtained supporting the general concept of alternating access for a variety of membrane transporters, demonstrating that this mechanism has been evolutionarily conserved” (i.e., unevolved). Such a statement clearly begs the question of evolution. It also leaves unanswered the question of how the first primitive microbe could have avoided death by poison without the ability to actively, effectively, pump toxins outside its protective walls.
How did an unguided, purposeless process arrange twelve precisely-ordered, right-sized cooperating intermembrane helices of amino acids into a cup shape, provided a precise pocket for a sodium ion, figured out how to invert the cup to the inside just long enough to recognize and bind a toxic molecule, and then flip over and shuttle it out, and do this 25 times a second. Did this all happen in a single chance miracle or a string of chance miracles? Tell us also how all the other tens of thousands of molecular machines essential for life “emerged,” like the topoisomerases that fold DNA into compact shapes and separate the chromosomes, the winches that pull chromosomes apart, the molecular highways that transport the good cargo all throughout the cell, the DNA repair molecules, and much, much more. Neo-Darwinism is utterly incapable of standing up to these findings about precision molecular machines in the cell.
Structure of a cation-bound multidrug and toxic compound extrusion transporter 2
Cellular export of toxins and substrates is a fundamental life process. MATE transporters are involved in a variety of important biological functions across all kingdoms of life.In mammals they export a structurally diverse array of xenobiotic cations in the liver and kidney, influencing the plasma concentrations of many drugs, including metformin, a widely prescribed type 2 diabetes medication, thereby mitigating therapeutic efficacy. Bacterial MATE transporters function primarily as xenobiotic efflux pumps and can confer resistance to tigecycline, a new glycylcycline-class antibiotic developed to overcome methicillin-resistant and vancomycin-resistant Staphylococcus aureus. MATE transporters use either H1 or Na1 gradients across the membrane to drive substrate export, although the coupling mechanism is not well understood.