The Peak District Midge Plague

Where I live on the edge of the Peak District we’ve recently had a burst of midges, resulting in a mass biting that led to Tesco selling out of creams and lotions for treating bites. That didn’t bother me (although it really bothered my wife), because I hardly ever get bitten. Why might that be? According to James Logan from Rothamsted Research, the answer  (for Culicoides impunctatus at least) is probably that I smell funny [1].

Comparing human odour extracts, several compounds were found to differ between those bitten and those not. The repellant activity of some was confirmed in behavioural assays. Two particular compounds showed activity: geranylacetone (PB) and 6-methyl-5-hepten-2-one (PB), both of which can be found in the insecty parts of PheroBase (hence PB), a pheromone database.

An excellent piece of work. Similar experiments have also been fruitful on mosquitoes [2].

[1]  Logan JG, Seal NJ, Cook JI, Stanczyk NM, Birkett MA, Clark SJ, Gezan SA, Wadhams LJ, Pickett JA, Mordue AJ. Identification of human-derived volatile chemicals that interfere with attraction of the Scottish biting midge and their potential use as repellents. J Med Entomol. 2009 Mar;46(2):208-19. PMID:19351071

[2] Logan JG, Birkett MA, Clark SJ, Powers S, Seal NJ, Wadhams LJ, Mordue Luntz,AJ, Pickett JA. Identification of human-derived volatile chemicals that interfere with attraction of Aedes aegypti mosquitoes. J Chem Ecol. 2008 Mar;34(3):308-22. Epub 2008 Feb 29. PMID: 18306972

Methylmercury uptake by LAT1

Methylmercury accumulates as it moves up the food chain from one predator to the next, which, for a top predator like humans (the carnivorous chaps at any rate), is A Bad Thing as it is quite horribly neurotoxic. In the course of my transporter work I came across some nice papers [1,2] explaining how the large amino acid transporter (LAT1, consisting of two parts encoded by SLC7A5 and SLC3A2) is responsible for the uptake of methylmercury (reportedly approaching 100% bioavailability). The neurotoxic effects probably wouldn’t be as severe if LAT1 wasn’t so active at the blood-brain barrier.

For methylmercury to be transported by LAT1 it must first be complexed by L-cysteine. It isn’t a substrate when not complexed, which is probably true of most heavy metals (cisplatin uptake via the copper transporter CTR1 being another example [3] – CTR1 mutations play a major role in cisplatin resistance). D-cysteine also can form a complex with methylmercury, but interestingly this complex isn’t a substrate of LAT1. So if your planning to eat mercury-laden fish, perhaps a spoonful of D-cysteine might help? (Not to be taken as medical advice).

The main treatment for mercury poisoning is chelation therapy using dimercaptosuccinic acid, which looks an awful lot like cysteine. Another (somewhat atypical) example of a drug exhibiting metabolite-likeness [4].

1: Simmons-Willis TA, Koh AS, Clarkson TW, Ballatori N. Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. Biochem J. 2002 Oct 1;367(Pt 1):239-46. PMID:12117417

2: Yin Z, Jiang H, Syversen T, Rocha JB, Farina M, Aschner M. The methylmercury-L-cysteine conjugate is a substrate for the L-type large neutral amino acid transporter. J Neurochem. 2008 Nov;107(4):1083-90. Epub 2008 Sep 13. PMID:18793329

3: Song IS, Savaraj N, Siddik ZH, Liu P, Wei Y, Wu CJ, Kuo MT. Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells. Mol Cancer Ther. 2004 Dec;3(12):1543-9. Erratum in: Mol Cancer Ther. 2005 May;4(5):864. PMID:15634647 

4: Dobson PD, Patel Y, Kell DB. ‘Metabolite-likeness’ as a criterion in the design and selection of pharmaceutical drug libraries. Drug Discov Today. 2009 Jan;14(1-2):31-40. Epub 2008 Dec 26. Review. PMID:19049901