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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 gazelles, kangaroo rats
– Whales, dolphins
– Polar bears
• But no more bizarre than your car...
Bizarre Biochemistry
There’s 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 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!
Bizarre Biochemistry
Why are there blondes in Italian
• 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
Bizarre Biochemistry
The Birth of Venus by Sandro Botticelli
Bizarre Biochemistry
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 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
Bizarre Biochemistry
Atropa belladonna
Deadly Nightshade
Belladonna - literally
“beautiful woman”
Bizarre Biochemistry
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
Bizarre Biochemistry
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
Bizarre Biochemistry
Bizarre Biochemistry
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
Bizarre Biochemistry
Diaphorase in normal blood
quickly reduces metHb to Hb
But diaphorase in “blue
blood” is unable to reduce
metHb effectively
Bizarre Biochemistry
Cawein needed a “cure” that was
reliable, safe, available and easy to use he decided to try a common dye:
Methylene Blue
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.”
Bizarre Biochemistry
The reaction of methemoglobin
with the colorless, reduced
leucomethylene blue returns the
hemoglobin to its normal (red)
Bizarre Biochemistry
• The youngest daughter of Czar
Nicholas II
• Did she survive assassination?
• Anna Anderson claimed to be
• Anderson died in 1984 and was
cremated, so the DNA that
might have told the tale was
Bizarre Biochemistry
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?
Bizarre Biochemistry
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
Bizarre Biochemistry
Dicoumarol formation:
Plant maceration at harvest 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 activation and
must be recycled
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
• The toxins have been
useful tools in medical
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+ channels
• All of these cause paralysis and death in the
Bizarre Biochemistry
• 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?
Bizarre Biochemistry
TCA Cycle
Bizarre Biochemistry
Did Life Begin on Fool’s Gold?
• The tricarboxylic acid cycle in metabolism
oxidizes carbon and gives off CO2
• Sugars, Fats, ProteinsAcetateCO2
• If you could run it in reverse, you would
accumulate CO2 and reduce carbon!
• CO2Sugars, 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 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
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!
Bizarre Biochemistry
Bizarre Biochemistry
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
Bizarre Biochemistry
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
Bizarre Biochemistry
Bizarre Biochemistry
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 + nitrocellulose + sawdust =
Bizarre Biochemistry
Why does nitro alleviate pain??
• For more than a hundred years, no one
• 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 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
Bizarre Biochemistry
Smooth Muscle Relaxation
Bizarre Biochemistry
A phosphodiesterase inhibitor
• 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3propyl-1H-pyrazolo [4,3-d]pyrimidin-5-yl)4-ethoxyphenyl]sulfonyl]-4methylpiperazine
• aka sildenafil
• aka Viagra
Bizarre Biochemistry
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