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Monday, September 1, 2008

Antimicrobial Heparin-binding Domains

Antimicrobial Digestion

Stomach enzymes produce antimicrobial peptides and intestinal enzymes inactivate heparin-binding domains of pathogens

The human digestive systems exhibits some amazing adaptations -- it can excise heparin-binding domains from ingested proteins and use them as antimicrobial peptides to inactivate ingested bacteria. Then in subsequent enzymatic steps in the intestines, the heparin-binding domains that otherwise could be used to adhere bacteria to the heparan sulfate proteoglycans of the intestinal lining, are chopped into inactive peptide fragments.

I was trying to find a cheap heparin-binding protein to use for a variety of research projects and finally found it in the form of whey lactoferrin. This protein is available in a relatively pure form for about $1 per milligram. Alternatively, I could buy it as a nutriceutical in 250 mg capsules for $0.50 per capsule or 1/500th the cost. My next step was to purify the cheap lactoferrin by binding it to chromatography beads with attached heparin. The lactoferrin stuck to the beads and other contaminating material was washed away. Finally, pure lactoferrin was released by increasing the salt concentration of the wash solution. My goal was to use proteolytic enzymes to hydrolyze the lactoferrin and produce peptide fragments containing heparin-binding domains. I naively pasted the known amino acid sequence of bovine lactoferrin into a website that would predict the cleavage locations of numerous proteases along the lactoferrin molecule. Amazingly, pepsin, the stomach protease, released a couple of peptides with heparin-binding domains, e.g. KCRRWQWRMKK, whereas trypsin, the intestinal protease, degraded all of the heparin-binding domains. I had a simple procedure for producing the peptides I wanted, but I also learned something about the beauty of the digestive system.

It took me a while to realize the utility of the alternative proteases. Production of heparin-binding peptides by pepsin enhances the sterilization of meals, because the heparin-binding domains are also generally antimicrobial. In fact, most antimicrobial peptides secreted by the skin or venom of a wide variety of organisms from primates to poison dart frogs have heparin-binding sequences. Degradation of heparin-binding domains by trypsin in the intestines is also advantageous, because numerous bacteria (e.g. E. coli O157;H7) and viruses (e.g. HIV and avian flu) use heparan sulfate regions of gut proteoglycans as receptors to immobilize these pathogens on the surface and initiate infections. Some toxins that rely on heparin-binding are also inactived in the intestines.

6 comments:

Stipetic said...

As far as you know, is this why ingested venom (for example, rattlesnake venom) is not problematic? Or is it because the venom is acid labile?

Dr. Art Ayers said...

Poisonguy,
Yeah, venoms, stings, etc. are just proteins. Most are enzymes that work directly on extracellular molecules. In some cases, a toxin, e.g. ricin, will bind to surface components of a cell and then act enzymatically after it is internalized. The combination of proteases and polysaccharides to coat the gut provide protection. Some of the enzymes may be inactivated by the low pH, but since they are extracellular proteins, they are more tolerant.

Thanks for the questions.

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