pyruvate kinase deficiency,
firstly identified in the
early 60s by Valentine
and coworkers is the most
frequent enzyme abnormality
of the glycolytic pathway,
nonspherocytic haemolytic anemia.
The disease is transmitted as
an autosomal recessive trait,
clinical symptoms usually occurring
in compound heterozygotes for two
mutant alleles, and in homozygotes,
restricted to a limited number
of cosanguineous families.
The degree of haemolysis
ranging from very mild or
fully compensated forms
to life-threatening neonatal
anemia and jaundice,
necessitating exchange transfusions.
PK deficiency has a worldwide
Over 400 cases have been described,
but many more remain unreported.
The prevalence, as assessed
by gene frequency studies,
has been estimated
to be one to 20,000
in the general wide population.
Erythrocyte PK is synthesized under
the control of the PK-LR gene,
located on chromosome 1.
In this presentation, we will
first consider the enzyme structure
and function, followed by
and clinical, hematological,
and diagnostic aspects
of PK deficiency.
The relation between
and disease severity and
the treatment options
will also be considered.
Pyruvate kinase is a
key glycolytic enzyme
that catalyzes the
from phosphoenolpyruvate, PEP, to
ADP, yielding pyruvate and ATP,
and requires potassium and magnesium
or manganese ions for activity.
The reaction is the last step
of the glycolytic pathway
and is essentially reversible
under physiological conditions.
is thought to be the major
regulatory enzyme of glycolysis.
Moreover, the substrate PEP
and the product pyruvate
being involved in a number
of energetic and biosynthetic
pathways, a tight
regulation of PK activity
turns out to be of great importance,
not only for glycolysis itself,
but also for the entire
PK deficiency leads to ATP
depletion that ultimately
affects the viability of the cell.
Moreover, PK deficiency
results in the accumulation
of the glycolytic intermediates
proximal to the metabolic block.
In particular, 2,3-DPG levels
that may increase up to three-fold
and further impair the
glycolytic flux through
the inhibition of hexokinase.
PK is an homotetramer
in almost all organisms.
Also, it may exist in different
forms, from monomer to decamer.
A high degree of structural homology
among PKs from different species
has been reported.
Crystal structures have
been published for PKs
from cat and rabbit muscle,
Escherichia coli, yest, Leishmania
mexicana, and human erythrocyte.
These structures resemble each other
in that each subunit is organized
into three principal domains.
In A domain with beta
alpha-8 viral topology,
a beta stranded B domain, inserted
between strand beta-3 and helix
alpha-3 of the A
domain, and C domain
with an alpha plus beta topology.
With the exception of prokaryotes, a
full, small domain corresponding to
the end terminus is also present.
The residuals forming
the catalytic site
are localized in the cleft
between the A and B domains.
And they are mostly
provided by the sixth
and eight loops of the A domain.
The crystal structure shows that
the four subunits of the tetramer
are assembled to form
a symmetric oligomer.
The inter-subunit interactions
define two large contact areas,
the A, A-prime interface involves
the A domains of subunits
related by the vertical axis.
Whereas the C, C-prime
the C domains of
along the horizontal axis.
The multi-domain architecture of PK
is instrumental to the regulation