Wheat and lactose and Cordain

In the comments thread of another post "g" pointed me to this ref. It's very interesting about WGA (Wheat Germ Agglutinin) hitting the nuclear pore, so stopping all sorts of cell signaling traffic. But this business about lactase is very dubious.

From here on down the inverted coma bits are direct quotes from Cordain, the other bits are me. EGF-R is epidermal growth factor receptor, a cell signaling and growth regulating receptor.


"Once in gut cells (enterocytes) WGA gains access to the circulation via the lymph and is not removed from circulation by the liver or by gamma globulins. Hence, within an hour of consumption WGA is found in plasma in physiological meaningful concentrations (as high as 5ug/ml). Because EGF-R are found on virtually all cells in the body, WGA now can enter the cellular compartment of all cells in the body. Once within cells, WGA wreaks more havoc by binding a structure called the nuclear pore and thereby impedes or prevents the cytosolic transport of the vitamin D receptor and its ligand (1,25 hydroxyvitamin D3) to the nucleus which results in impaired vitamin D utilization and systemically will result in rickets if high dietary levels of whole wheat are chronically consumed."

This is very interesting, it looks like Cordain follows Pusztai's line of thinking on systemic absorption of WGA and is citing a new toxicity. This time via the vitamin D receptor and rickets. Nice.

However Cordain always seems to blot his copybook. Let's try and make head or tail of the next paragraph. It goes like this:

"Lactase is an enzyme technically known as lactase phorizin hydrolase or LPH. LPH [lactase] is a carbohydrate enzyme (glycosidase) belonging to the beta galactosidase family and it catalyzes the sugar beta-galactosidase in addition to catalyzing lactose, the sugar in milk."

What does this mean? Beta-galactosidase is not a sugar, it's the enzyme family to which lactase belongs, as Cordain has just told us. So this has to be a typo, which leaves us in the dark as to exactly what Cordain intended to say. Was it beta galactosamine he was talking about, as in the next sentence? Is he suggesting that lactase either breaks down or synthesises beta galactosamine?

"Beta galactosamine is a key structural sugar in the EGF-R."

I'll take that on trust.

"Hence the adult retention of LPH [lactase] was strongly selected in Neolithic N. European populations because it could compete with WGA for the EGF-R and thereby, in effect, displace WGA from the EGF-R."

Now what does this mean? Is he saying lactase binds directly to the EGF-R on the gut to stop the ingress of WGA in to enterocytes and thus in to the lymphatics and systemic circulation?

"WGA preferentially binds the sugar n-acetylglucosamine which is also present in the EGF-R."

This is true (taking on trust that n-acetylglucosamine is present on EGF-R).

"Consequently, the evolutionary selection for LPH [lactase] occurred as direct competition for the EGF-R rather than LPH binding WGA directly."

The implication from this is that lactase is binding to beta galactosamine on EGF-R of enterocytes and this binding is stopping WGA from binding to the n-acetylglucosamine of same EGF-R molecule. Cordain doesn't mention the gut cell surface as the site of interaction but never suggests that lactase ever reaches significant concentrations in the systemic circulation, so let's stick with gut. He finishes:

"In summary then, the simulataneous selection for LPH [lactase] and dermal de-pigmentation were two changes in the genome of Northern Europeans that were a direct evolutionary response to increased consumption of whole wheat"

I can buy the need for pale skin on a Vitamin D deficient diet in Northern climates. Grains are the pits for deficiency diseases. The nuclear pore blockade should actually predict that WGA consuming people need a higher absolute level of vitamin D for health. I wonder if this is true?

But I don't buy the lactase part.

Lactase is part of a family of enzymes for cleaving terminal sugar moieties. Why should it just sit on the EGF-R to keep WGA off? I can believe it might visit EGF-R briefly to chop up the beta galactosamine (but why?) whenever it's not actively chopping up lactose, but would it sit there attached to beta galactosamine (without cleaving it?) when it should really be getting on with its next lactose cleavage job? Also, would a mammal put in to its infant food a sugar which induces lactase production if that lactase was then going to slip away and sit on the glycation moiety of one of its growth factor receptors? EGF-R is there for cell signaling and the beta galactosamine is a "key structural sugar", not decoration. Maybe it actually needs its beta galactosamine component to work.

On the other hand wheat is looking for a free ride for its seeds. WGA is its lectin, which uses n-acetylglucosamine moieties on cell surfaces specifically to become endocytosed. Once inside the cell all WGA needs to do is produce as much damage as possible, so disrupting digestion, which will maximise the chances of any still undamaged wheat seeds being passed through the gut in tact. Then these can seed the next piece of clear ground which the herbivore poops on.

I notice the email comment is dated Feb 2006. It's now late Jan 2008 and the publication has not hit Pubmed yet. Maybe that one final experiment didn't work?

What's wrong with WGA damaging everyone, full stop? And that lactase persistence is rapidly selected for in people who keep cows for milk, otherwise they get gut rot? Do the Maasai loose lactase when weaned from their mothers because they don't eat wheat? They would no more eat wheat than Cordain would live on sour cow's milk, bulked up when necessary with fresh cow's blood!

Yummie.

Peter

PS I'm surprised Cordain didn't suggest a statin to raise vitamin D levels!