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http://ocw.mit.edu 5.111 Principles of Chemical Science
See lecture 21 and 22 notes for acid-base equilibrium and lecture 22 and 23 notes for
an introduction to buffers.
A buffer solution is any solution that maintains an approximately constant pH despite
small additions of acid and base. The pH of a buffer is maintained by a mixture of weak
conjugate acids and bases, which provides a source or sink for protons.
Blood is buffered in the pH range 7.35-7.45 Buffering agents in blood: H2CO3/HCO3- (carbonic acid/bicarbonate) Example from Lecture 23 video: Effects on Blood pH from Vitamin B12 Deficiency
The buffering capacity of a buffered solution can be overcome by the addition of
excessive acid or base.
An instance of too much acid affecting the pH of blood occurs in the disease
methylmalonic aciduria, a metabolic disorder in which methylmalonic acid builds up in
the blood and overcomes the H2CO3/HCO3- buffering capacity.
In healthy individuals, fatty acids (fats) are converted into energy through the series of
steps shown below. Enzymes catalyze each of these steps, and the enzyme
methylmalonyl-CoA mutase (MUT), which requires vitamin B12 binding for activity,
catalyzes the conversion of methylmalonyl-CoA to succinyl-CoA. In the absence of
sufficient vitamin B12 or in cases where vitamin B12 cannot bind to MUT,
methylmalonyl-CoA is instead converted to methylmalonic acid, and buildup of this acid
can result in a lowering of blood pH.
methylmalonyl-CoA methylmalonic acid
O MUT catalyzed succinyl-CoA C
OH CH3 citric acid cycle
wild-type MUT enzyme (in white)
with vitamin B12 (in red) bound (excessive acid build up) energy In methylmalonic aciduria, the MUT-catalyzed step cannot occur, resulting in a buildup of
acid instead of the conversion of fatty acids into energy.
The disease methylmalonic aciduria can be caused by insufficient vitamin B12 intake.
However, it is most often caused by a genetic mutation in the gene encoding the MUT
enzyme. A single amino acid substitution from a glycine (the smallest amino acid) to an
arginine (a much larger amino acid) can destroy all MUT activity. Using X-ray crystallography, scientists determined that the glycine-to-arginine mutation
occurs in the B12 binding pocket, blocking vitamin B12 binding (see pictures A and B
below). This explains why it is not effective to treat individuals with methylmalonic
aciduria with high doses of B12, since the B12 cannot bind to MUT. Using this
information, scientists are now looking into treatment with a truncated B12 mimic that can
bind in the blocked pocket of the mutant MUT enzyme (see picture C below). This
truncated B12 can partially restore MUT activity, and may lead to a successful treatment
for methylmalonic aciduria. The MUT enzyme is shown in white, the arginine residue in the mutant enzyme is shown
(blocking the binding pocket) in blue, and vitamin B12 is shown in red. ...
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This note was uploaded on 03/02/2012 for the course CHEM 5111 taught by Professor Vogel during the Fall '08 term at MIT.
- Fall '08