bizarre biochemistry

Bizarre Biochemistry

Bizarre BiochemistryScience Lecture Series

October 6, 1999University of San Diego


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 gazelles, kangaroo rats– Whales, dolphins– Polar bears

• But no more bizarre than your car...


There’s not as much yellow snow in the Arctic as you might think!


Turning Fat into Water

• Fats (and gasoline) contain highly reduced carbon (lots of electrons and hydrogens)

• “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!


Why are there blondes in Italian paintings?

• Blonde hair is rare in Italy, but the Vikings or other northern Europeans may have been known to the Italians

• But hydrogen peroxide was not known until about 1850, and L’Oréal much later….

• Italian women may have relied on plants!• Peroxisomes contain H2O2, and the sun can

help


The Birth of Venus by Sandro Botticelli


La Primavera by Sandro Botticelli


Peroxisomes, like lysosomes, contain powerful enzymes that use molecular oxygen and generate peroxide.


“Beautiful Eyes” - at a price

• Atropa belladonna (Deadly nightshade) makes atropine, an “anticholinergic” agent

• Used to 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


Atropa belladonna

Deadly Nightshade

Belladonna - literally

“beautiful woman”


A model of the acetylcholine receptor

by Eberhard von Kitzing of the Max Planck Inst. in Heidelberg

Atropine prevents the channel from opening - thus blocking nerve impulses


The Blue Fugates of Kentucky

• In 1820, Martin Fugate settled 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


What is Methemoglobinemia?

• 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


Diaphorase in normal blood quickly reduces metHb to Hb

But diaphorase in “blue blood” is unable to reduce metHb effectively


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 mg 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.”


The reaction of methemoglobin with the colorless, reduced leucomethylene blue returns the hemoglobin to its normal (red) form.


Anastasia

• The youngest daughter of Czar Nicholas II

• Did she survive assassination?• Anna Anderson claimed to be

Anastasia• Anderson died in 1984 and was

cremated, so the DNA that might have told the tale was destroyed


Making a lot from a little...

• A piece of Anderson’s intestine remained in a freezer in a Charlottesville hospital

• Too little DNA for genetic analysis• With the polymerase chain reaction, a small

amount of DNA can be used to make a lot!• The analysis was done after much ado• Was she or wasn’t she….?• Can you spell Franziska Schanzkowska?


Coumadin/Warfarin - Agent of Life and Death

• Karl Paul Link wondered why cattle bled excessively from wire cuts and dehorning

• He identified dicoumarol 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


Dicoumarol formation:

Plant maceration at harvest facilitates coumarin formation from melilotoside. Molds growing in wet storage conditions can convert coumarin to the anticoagulant dicoumarol.


Vitamin K activates carboxylation of glutamate residues in proteins that trigger blood clotting

Vitamin K is oxidized in this activation and must be recycled continuously.

Warfarin/Coumadin blocks this recycling, preventing the formation of normal blood-clotting proteins.


Cone Snails - Bizarre Killers

• Marine snails found in reefs around the world

• They prey on fish, injecting a cocktail of neurotoxins

• The toxins have been useful tools in medical research


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+ channels• All of these cause paralysis and death in the

victim


Rotenone

• Amazon natives don’t give the fish an even break (they can’t 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 does rotenone work?


Glycolysis

Sugars

TCA Cycle

ElectronTransport

OxidativePhosphorylation


Did Life Begin on Fool’s Gold?

• The tricarboxylic acid cycle in metabolism oxidizes carbon and gives off CO2

• Sugars, Fats, ProteinsAcetateCO2

• If you could run it in reverse, you would accumulate CO2 and reduce carbon!

• CO2Sugars, Fats, Proteins


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 could also act as a

catalyst in the reactions of metabolism• Many modern metabolic enzymes have

iron/sulfur clusters, a vestige of FeS2!


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!• How 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!


Male Pseudohermaphroditism

• Testosterone plays a role in development of sex characteristics in the fetal human

• Genetic males 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


The source of the problem

• Testosterone is synthesized from cholesterol by a series of five enzyme 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


Alfred Nobel• Had “angina pectoris” - chest 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


Why does nitro alleviate pain??

• For more than a hundred years, 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


When N-O means 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


Arg

GTPcGMPGMP

Smooth Muscle Relaxation

PDEX


A phosphodiesterase inhibitor

• 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine

• aka sildenafil• aka Viagra


Viagra


Mechanism of Viagra

• Inhibitor of cGMP phosphodiesterase• cGMP levels stay high for long times• Smooth muscle of blood vessels is relaxed

for extended periods

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