Lactate Dehydrogenase

Lactate Dehydrogenase
June 2008 Molecule of the Month by David Goodsell

doi: 10.2210/rcsb_pdb/mom_2008_6 (PDF Version, ePub Version )
Keywords: aerobic exercise, L-lactate dehydrogenase activity, oxidation reduction, anaerobic
glycolysis, isozymes, fermentation

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Introduction
Lactate dehydrogenase is a safety valve in our pipeline of energy production. Most of the time,
our cells break down glucose completely, releasing the carbon atoms as carbon dioxide and the
hydrogen atoms as water. This requires a lot of oxygen. If the flow of oxygen is not sufficient,
however, the pipeline of energy production gets stopped up at the end of glycolysis. Lactate
dehydrogenase is the way that cells solve this problem, at least temporarily.
Aerobic exercise
When we exercise at a normal pace, our cells get plenty of oxygen and sugar is broken down
quickly and efficiently. However, during sprints or other over-exertions, there isn't enough
oxygen to go around. In this case, our cells use glycolysis as their primary source of energy, As
part of glycolysis, hydrogen from glucose is placed on NAD+ to form NADH. Normally, these
hydrogen atoms are then transferred to oxygen to form water. If oxygen isn't available, the
NADH builds up and there isn't enough NAD+ to continue using glycolysis to make ATP. That's
where lactate dehydrogenase steps in: it combines pyruvate and NADH, producing lactic acid
and NAD+. The NAD+ can then be recycled to do another round of glycolysis, quickly
producing more energy for the sprint. However, lactic acid builds up and in a matter of a minute
or so, you have to stop and let your body recover. As you catch your breath, your body converts
the lactic acid back to pyruvate, where it enters your normal flow of aerobic energy production.
Mix and Match
Our cells build two major types of lactate dehydrogenase: the M form and the H form (there is
also a third form that is only made in sperm). These are very similar in size and shape, but they
have different catalytic properties. The M form, which is the major form in your large skeletal
muscles, is best at converting pyruvate to lactate. It stands ready to get to work if the muscles
need to perform anaerobic exercise. The H form, on the other hand, is better at the opposite
reaction, converting lactate to pyruvate. It is the major form in the heart, which has a constant
supply of oxygen and can easily use lactate as an aerobic source of energy. The two types are so
similar in structure that they form complexes with a mixture of both types, for instance, with two
H chains and two M chains. In this way, different cells can tailor their lactate dehydrogenases to
fit their current needs. The molecule shown here, from PDB entry 3ldh, is the form with four
identical M chains.

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Fermentation
Some bacteria obtain most of their energy by conversion of glucose into lactose. This process is
called fermentation, and you have probably experienced the results of it at the dinner table.
Fermenting bacteria are used to convert milk into yogurt and fermented lactic acid is an
important part of the sharp flavors of sauerkraut and sourdough bread. The bacterial lactose
dehydrogenase shown here is an allosteric enzyme. Binding of fructose 1,6-bisphosphate, one of
the molecules formed in the early steps of glycolysis, causes the enzyme to change into an active
shape. Remarkably, PDB entry 1lth, shown here, contains two separate enzyme molecules, one
in the active state (left) and one in the inactive state (right).

Exploring the Structure
Jmol 1

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Exploring the Structure
The protozoan parasites that cause malaria are thought to rely on glycolysis for most of their
energy during part of their cycle of infection. Researchers are now looking for drugs to block the
action of lactate dehydrogenase as a way of attacking these parasites and curing the infection.
The structure shown here (PDB entry 1cet) has four molecules of chloroquine bound in the
active sites of the lactate dehydrogenase found in the Plasmodium parasite. Chloroquine is one of
the major drugs used to treat malaria, however, its major site of action probably isn't at this
enzyme; instead, it is thought to block the unusual methods that the parasite must use to feed on
blood. But researchers are exploring many other anti-malarial molecules that target lactate
dehydrogenase, as seen in other PDB entries such as 1t24, 1t25, and similar structures.

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Additional reading about lactate dehydrogenase
D. L. Nelson and M. M. Cox (2000) Lehninger Principles of Biochemistry. Worth Publishers.
M. T. Madigan, J. M. Martinko and J. Parker (2000) Brock Biology of Microorganisms. Prentice
Hall.
J. A. Read, K. W. Wilkinson, R. Tranter, R. B. Sessions and R. L. Brady (1999) Chloroquine
binds in the cofactor binding site of Plasmodium falciparum lactate dehydrogenase. Journal of
Biological Chemistry 274, 10213-10218.
S. Iwata, K. Kamata, S. Yoshida, T. Minowa and T. Ohta (1994) T and R states in the crystals of
bacterial L-lactate dehydrogenase reveal the mechanism for allosteric control. Structure 1, 176-
185.
J. J. Holbrook, A. Liljas, S. J. Steindel and M. G. Rossman (1975) Lactate Dehydrogenase. In
"The Enzymes," P. D. Boyer, editor. Academic Press. Volume XI, pages 191-292.

Discussed Structures

lactate dehydrogenase

lactate dehydrogenase (LDH)

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June 2008 Molecule of the Month by David Goodsell

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