MOLECULE OF THE MONTH:

www.pdb.org
info@rcsb.org LACTATE DEHYDROGENASE doi: 10.2210/rcsb_pdb/mom_2008_6
Lactate dehydrogenase is
a safety valve in our
pipeline of energy pro-
duction. 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 suffi-
cient, however, the
pipeline of energy pro-
duction gets stopped up
at the end of glycolysis.
Lactate dehydrogenase is
the way that cells solve
this problem, at least
temporarily.

Aerobic exercise Mix and Match

About the
RCSB PDB Molecule of the Month
Using selected molecules from the PDB
archive, each feature includes an
introduction to the structure and func-
tion of the molecule, a discussion of its
relevance to human health and welfare,
and suggestions for viewing and
accessing further details.
The RCSB PDB Molecule of the Month
is read by students, teachers, and scien-
tists worldwide at www.pdb.org.
This edition was written and illustrated
by David S. Goodsell (RCSB PDB and
The Scripps Research Institute).
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 glycol-
ysis to make ATP. That's where lactate dehy-
drogenase steps in: it combines pyruvate and
NADH, producing lactic acid and NAD+.
The NAD+ can then be recycled to do anoth-
er 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 produc-
tion.
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 prop-
erties. The M form, which is the major form
in your large skeletal muscles, is best at con-
verting 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, con-
verting lactate to pyruvate. It is the major
form in the heart, which has a constant sup-
ply 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.
 LACTATE DEHYDROGENASE
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It is supported by funds from the

National Science Foundation, the
National Institute of General Medical
Sciences, the Office of Science,
Department of Energy, the National
Fermentation
Library of Medicine, the National Some bacteria obtain most of their energy by conversion of glucose into lactose. This process is
Cancer Institute, the National Center called fermentation, and you have probably experienced the results of it at the dinner table.
for Research Resources, the National
Institute of Biomedical Imaging and
Fermenting bacteria are used to convert milk into yogurt and fermented lactic acid is an impor-
Bioengineering, the National Institute tant part of the sharp flavors of sauerkraut and sourdough bread. The bacterial lactose dehydro-
of Neurological Disorders and Stroke genase shown here is an allosteric enzyme. Binding of fructose 1,6-bisphosphate, one of the
and the National Institute of Diabetes
& Digestive & Kidney Diseases.
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
The RCSB PDB is a member of in the active state (left) and one in the inactive state (right).
the worldwide PDB
(wwPDB; www.wwpdb.org).

Exploring the Structure

Additional Reading
D.L. Nelson, M.M. Cox (2000) Lehninger
Principles of Biochemistry. Worth Publishers.
M. T. Madigan, J. M. Martinko, J. Parker
(2000) Brock Biology of Microorganisms.
Prentice Hall.
J.A. Read, K.W. Wilkinson, R. Tranter, R.B.
Sessions, 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,
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.
The protozoan parasites that cause malaria are
thought to rely on glycolysis for most of their ener-
gy during part of their cycle of infection.
Researchers are now looking for drugs to block the
action of lactate dehydrogenase as a way of attack-
ing 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.
References:
3ldh: White, J.L., Hackert, M.L., Buehner, M., Adams, M.J., Ford, G.C., Lentz Jr., P.J., Smiley, I.E., Steindel, S.J., Rossmann,
M.G. (1976) A comparison of the structures of apo dogfish M4 lactate dehydrogenase and its ternary complexes. J.Mol.Biol. 102:
759-779.
1lth: S. Iwata, K. Kamata, S. Yoshida, T. Minowa, T. Ohta (1994) T and R states in the crystals of bacterial L-lactate dehydrogenase
reveal the mechanism for allosteric control. Nat.Struct.Biol. 1: 176-185.
1t24: A. Cameron, J. Read, R. Tranter, V.J. Winter, R.B. Sessions, R.L. Brady, L. Vivas, A. Easton, H. Kendrick, S.L. Croft, D. Barros,
J.L. Lavandera, J.J. Martin, F. Risco, S. Garcia-Ochoa, F.J. Gamo, L. Sanz, L. Leon, J.R. Ruiz, R. Gabarro, A. Mallo, F.G. de las Heras
(2004) Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity.
J.Biol.Chem. 279: 31429-31439.