Pyruvate kinase deficiency

Published on October 1, 2007 Updated on July 31, 2016   41 min

Other Talks in the Series: Protein Epidemiology

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Red cell pyruvate kinase deficiency, firstly identified in the early 60s by Valentine and coworkers is the most frequent enzyme abnormality of the glycolytic pathway, causing hereditary 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 varies widely, ranging from very mild or fully compensated forms to life-threatening neonatal anemia and jaundice, necessitating exchange transfusions. PK deficiency has a worldwide geographical distribution. 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.
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In this presentation, we will first consider the enzyme structure and function, followed by genetic characteristics and clinical, hematological, and diagnostic aspects of PK deficiency. The relation between molecular defect and disease severity and the treatment options will also be considered.
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Pyruvate kinase is a key glycolytic enzyme that catalyzes the transphosphorylation 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
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and is essentially reversible under physiological conditions. Together with phosphofructokinase, PK is thought to be the major regulatory enzyme of glycolysis. Moreover, the substrate PEP and the product pyruvate
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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 cellular metabolism. PK deficiency leads to ATP depletion that ultimately
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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.
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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
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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
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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 interface involves the C domains of subunits interacting along the horizontal axis. The multi-domain architecture of PK is instrumental to the regulation
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Pyruvate kinase deficiency

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