1、Bizarre Biochemistry,Bizarre Biochemistry,Science Lecture Series October 6, 1999 University of San Diego,Bizarre Biochemistry,Water - the Elixir of Life,“Whiskey is for drinking; water is for fighting over.” (Mark Twain) Life is bizarre in the desert, ocean & Arctic Consider: Camels, gerbils, Dorcas
2、 gazelles, kangaroo rats Whales, dolphins Polar bears But no more bizarre than your car.,Bizarre Biochemistry,Theres not as much yellow snow in the Arctic as you might think!,Bizarre Biochemistry,Turning Fat into Water,Fats (and gasoline) contain highly reduced carbon (lots of electrons and hydrogen
3、s) “Oxidation” of these molecules to CO2 requires that you put those electrons and Hs somewhere - and water results! One 16-C fatty acid 16CO2 + 130H2O But we pay $350/barrel for it!,Bizarre Biochemistry,Why are there blondes in Italian paintings?,Blonde hair is rare in Italy, but the Vikings or oth
4、er northern Europeans may have been known to the Italians But hydrogen peroxide was not known until about 1850, and LOral much later. Italian women may have relied on plants! Peroxisomes contain H2O2, and the sun can help,Bizarre Biochemistry,The Birth of Venus by Sandro Botticelli,Bizarre Biochemis
5、try,La Primavera by Sandro Botticelli,Bizarre Biochemistry,Peroxisomes, like lysosomes, contain powerful enzymes that use molecular oxygen and generate peroxide.,Bizarre Biochemistry,“Beautiful Eyes” - at a price,Atropa belladonna (Deadly nightshade) makes atropine, an “anticholinergic” agent Used t
6、o dilate pupils in eye exams Used by Italian women in ancient times to dilate pupils, making them “beautiful” but compromising their eyesight! It prevents opening of the nicotinic acetylcholine receptor, blocking nerve impulses,Bizarre Biochemistry,Atropa belladonna Deadly Nightshade,Belladonna - li
7、terally “beautiful woman”,Bizarre Biochemistry,A model of the acetylcholine receptorby Eberhard von Kitzing of the Max Planck Inst. in Heidelberg,Atropine prevents the channel from opening - thus blocking nerve impulses,Bizarre Biochemistry,The Blue Fugates of Kentucky,In 1820, Martin Fugate settled
8、 on Troublesome Creek in Kentucky He was blue Six generations later, there were many blue Fugates on the Cumberland Plateau Hematologist Madison Cawein perceived that the condition was hereditary - and he suspected methemoglobinemia,Bizarre Biochemistry,Bizarre Biochemistry,What is Methemoglobinemia
9、?,Hemoglobin, the oxygen-carrying protein in blood, contains Fe - normally Fe2+ Small amounts of Fe in Hb are occasionally oxidized to Fe3+, yielding methemoglobin The enzyme called diaphorase “repairs” the Hb, reducing Fe3+ to Fe2+ If diaphorase is defective, Fe3+ accumulates,Bizarre Biochemistry,D
10、iaphorase in normal blood quickly reduces metHb to HbBut diaphorase in “blue blood” is unable to reduce metHb effectively,Bizarre Biochemistry,Methylene Blue,Cawein needed a “cure” that was reliable, safe, available and easy to use - he decided to try a common dye:,He injected one patient with 100 m
11、g of methylene blue. Within minutes, the skin was pink!,He gave methylene blue tablets to each blue family, to take each day, because the effects are temporary and methylene blue is excreted in the urine.,One old mountain man confided to Cawein: “Doc, I can see that old blue running out of my skin.”
12、,Bizarre Biochemistry,The reaction of methemoglobin with the colorless, reduced leucomethylene blue returns the hemoglobin to its normal (red) form.,Bizarre Biochemistry,Anastasia,The youngest daughter of Czar Nicholas II Did she survive assassination? Anna Anderson claimed to be Anastasia Anderson
13、died in 1984 and was cremated, so the DNA that might have told the tale was destroyed,Bizarre Biochemistry,Making a lot from a little.,A piece of Andersons intestine remained in a freezer in a Charlottesville hospital Too little DNA for genetic analysis With the polymerase chain reaction, a small am
14、ount of DNA can be used to make a lot! The analysis was done after much ado Was she or wasnt she.? Can you spell Franziska Schanzkowska?,Bizarre Biochemistry,Coumadin/Warfarin - Agent of Life and Death,Karl Paul Link wondered why cattle bled excessively from wire cuts and dehorning He identified dic
15、oumarol in spoiled sweet clover hay as the anticoagulant He made anticoagulant coumarin derivatives One - warfarin - is now used as a rat poison Warfarin - renamed Coumadin - is a “blood thinner” for patients at risk for blood clots,Bizarre Biochemistry,Dicoumarol formation:,Plant maceration at harv
16、est facilitates coumarin formation from melilotoside. Molds growing in wet storage conditions can convert coumarin to the anticoagulant dicoumarol.,Bizarre Biochemistry,Vitamin K activates carboxylation of glutamate residues in proteins that trigger blood clotting,Vitamin K is oxidized in this activ
17、ation and must be recycled continuously.,Warfarin/Coumadin blocks this recycling, preventing the formation of normal blood-clotting proteins.,Bizarre Biochemistry,Cone Snails - Bizarre Killers,Marine snails found in reefs around the world They prey on fish, injecting a cocktail of neurotoxins The to
18、xins have been useful tools in medical research,Bizarre Biochemistry,Bizarre Conotoxins,Small, highly constrained peptides (10-30 amino acids long) Each targets a particular receptor protein -Conotoxins target acetylcholine receptor -Conotoxins target muscle Na+ channels -Conotoxins target Ca2+ chan
19、nels All of these cause paralysis and death in the victim,Bizarre Biochemistry,Rotenone,Amazon natives dont give the fish an even break (they cant afford to!) Before fishing, they beat the roots of trees on the riverbank This releases rotenone, which paralyzes the fish, making them easy targets How
20、does rotenone work?,Bizarre Biochemistry,Glycolysis,Sugars,TCA Cycle,Electron Transport,Oxidative Phosphorylation,ATP,Bizarre Biochemistry,Did Life Begin on Fools Gold?,The tricarboxylic acid cycle in metabolism oxidizes carbon and gives off CO2 Sugars, Fats, ProteinsAcetateCO2If you could run it in
21、 reverse, you would accumulate CO2 and reduce carbon! CO2Sugars, Fats, Proteins,Bizarre Biochemistry,Bizarre Biochemistry,How Would This Happen?,The conversion of iron sulfide and H2S to iron pyrite might drive the reaction FeS + H2S FeS2 (iron pyrite) + H2 G = -38 kJ/mol The surface of iron pyrite
22、could also act as a catalyst in the reactions of metabolism Many modern metabolic enzymes have iron/sulfur clusters, a vestige of FeS2!,Bizarre Biochemistry,Cellulose,Soft and flexible in cotton But extremely strong in trees What is the source of the strength? Hydrogen bonds - at about 25 kJ/mol! Ho
23、w much stabilization energy is there in the H-bonds in 1 cubic foot of oak? About 4000 kJ! Enough to keep a runner going for 6-7 hrs!,Bizarre Biochemistry,Bizarre Biochemistry,Male Pseudohermaphroditism,Testosterone plays a role in development of sex characteristics in the fetal human Genetic males
24、that produce too little testosterone in the testes are born with female characteristics At puberty, an increase in serum testosterone causes an increase in male hair growth patterns,Bizarre Biochemistry,The source of the problem,Testosterone is synthesized from cholesterol by a series of five enzyme
25、 reactions The last is the 17-hydroxysteroid dehydrogenase, which converts 4-androstenedione to testosterone Affected individuals have mutations in this enzyme in the testes With a defective enzyme, no testosterone,Bizarre Biochemistry,Bizarre Biochemistry,Alfred Nobel,Had “angina pectoris” - chest
26、pain His doctor prescribed nitroglycerin This was a bit like carrying coals to Newcastle - and then eating them. Because Nobel had made his fortune from nitroglycerin Nitroglycerin + nitrocellulose + sawdust =,Dynamite,Bizarre Biochemistry,Why does nitro alleviate pain?,For more than a hundred years
27、, no one knew! In the 1970s, Robert Furchgott struggled to understand contraction of smooth muscle and decided that the endothelium was producing an agent that made vascular smooth muscle relax In 1977 (at UVa), Ferid Murad showed that nitroglycerin broke down to NO,Bizarre Biochemistry,When N-O mea
28、ns Yes,Furchgott and Louis Ignarro eventually showed that EDRF and NO were the same NO, made from arginine, binds to guanylyl cyclase, causing a 400-fold increase in formation of cGMP cGMP is a signal molecule that activates or inhibits many cellular processes cGMP is degraded by phosphodiesterases,
29、Bizarre Biochemistry,N-O,Arg,Guanylyl cyclase,N-O,N-O,GTP,cGMP,GMP,Smooth Muscle Relaxation,PDE,X,Bizarre Biochemistry,A phosphodiesterase inhibitor,1-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo 4,3-dpyrimidin-5-yl)-4-ethoxyphenylsulfonyl-4-methylpiperazine aka sildenafil aka Viagra,Bizarre Biochemistry,Viagra,Bizarre Biochemistry,Mechanism of Viagra,Inhibitor of cGMP phosphodiesterase cGMP levels stay high for long times Smooth muscle of blood vessels is relaxed for extended periods,Bizarre Biochemistry,
