Would not this article point to a PREdisease iron loading Pyruvate Kinase Deficiency .. ?
It seems to say the IRON itself CAUSES the deficiency.
It would then again evidence the possibility of a 'long term transfusion independent remission' by going LOWER than that one might think they 'need' to in order to generate the remission .. ?
Iron loading found in those with sickle-cell and now to Pyruvate Kinase Deficiency .. ?
Iron-Dependent Oxidative Inactivation with Affinity Cleavage of
Pyruvate Kinase.
Biol Trace Elem Res. 2009 Jan 24.
Murakami K, Tsubouchi R, Fukayama M, Qiao S, Yoshino M.
Department of Biochemistry, Aichi Medical University School of
Medicine,
Nagakute, Aichi, 480-1195, Japan.
Treatment of rabbit muscle pyruvate kinase with iron/ascorbate caused
an inactivation with the cleavage of peptide bond.
The inactivation or fragmentation of the enzyme was prevented by
addition of Mg(2+), catalase, and mannitol, but ADP and PEP the
substrates did not show any effect.
Protective effect of catalase and mannitol suggests that hydroxyl
radical produced through the ferrous ion-dependent reduction of oxygen
is responsible for the inactivation/fragmentation of the enzyme.
SDS-PAGE and TOF-MS analysis confirmed five pairs of fragments, which
were determined to result from the cleavage of the Lys114-Gly115,
Glu117-Ile118, Asp177-Gly178, Gly207-Val208, and Phe243-Ile244 bonds
of the enzyme by amino-terminal sequencing analysis.
Protection of the enzyme by Mg(2+) implies the identical binding sites
of Fe(2+) and Mg(2+), but the cleavage sites were discriminated from
the cofactor Mg(2+)-binding sites.
Considering amino acid residues interacting with metal ions and
tertiary structure, Fe(2+) ion may bind to Asp177 neighboring to
Gly207 and Glu117 neighboring to Lys114 and Phe243, causing the
peptide cleavage by hydroxyl radical.
Iron-dependent oxidative inactivation/fragmentation of pyruvate kinase
can explain the decreased glycolytic flux under aerobic conditions.
Intracellular free Mg(2+) concentrations are responsible for the
control of cellular respiration and glycolysis.
PMID: 19169653
---------------------
Lower Ferritin Concentrations Are Associated with Decreased Hemolysis
in Sickle Cell Disease Children without Iron Overload.
Blood (ASH Annual Meeting Abstracts) 2009 114: Abstract 2571
Oswaldo L Castro, MD1, Mehdi Nouraie, M.D., Ph.D.*,1, Lori Luchtman-
Jones, MD2, Xiaomei Niu, M.D.*,1, Caterina Minniti, M.D.*,3, Andrew D.
Campbell, MD4, Sohail R Rana, MD*,5, Gregory J. Kato, MD6, Mark
Gladwin, MD7 and Victor R. Gordeuk, MD1
1 Center for Sickle cell Disease, Howard University, Washington, DC,
USA,
2 Children's National Medical Center, Washington, DC, USA,
3 Vascular Medicine Branch, NHLBI, Bethesda, MD, USA,
4 Pediatric Hematology/Oncology, Univ. of Michigan Med. Ctr., Ann
Arbor, MI, USA,
5 Department of Pediatric and Child Health, Howard University
Hospital, Washington, DC,
6 Pulmonary and Vascular Medicine Branch, National Heart, Lung, and
Blood Institute, National Institutes of Health, Bethesda, MD, USA,
7 Division of Pulmonary, Allergy and Critical Care Medicine,
University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Abstract 2571
Poster Board II-548
The role of iron in the pathophysiology of sickle cell disease
(SCD) is complex and not fully understood.
Iron overload is associated with disease severity primarily
because multiple transfusions are linked to a severe SCD
clinical course.
Additionally, hemolysis, also associated with disease severity,
increases iron absorption.
Iron deficiency decreases red cell MCHC, which lowers Hb S
polymerization and thus may improve the clinical manifestations
of SCD.
Such a hypothesis is supported by our recent observation of a
homozygous SCD adult with iron deficiency anemia and a very low
hemolytic rate that increased dramatically with iron
supplementation.
This experience and similar case reports from the literature led
us to examine the relationship of ferritin levels with hemolysis
and other laboratory and clinical parameters in a group of non-iron
overloaded children with sickle cell disease.
All subjects in this analysis were enrolled in a prospective study
of the prevalence and significance of pulmonary hypertension in
children with SCD (PUSH).
Because of the known association of high serum ferritin with
multiple transfusions and with a severe clinical course in this
and other SCD populations, we excluded children who had ferritin
concentrations of 242 ng/ml or higher.
This cut-off value is 3 SDs above the geometric mean of the
ferritin concentrations in a group of 42 age, sex, and ethnicity
matched control children without SCD.
Hence the group of sickle cell children with ferritin levels of
< 242 ng/ml should include only those with iron deficiency or
with normal iron stores.
In this group of non-iron overloaded SCD children and
adolescents (median age 12 y, range 3–20 y), lower
serum ferritin was related to higher serum transferrin
and to lower serum iron and MCV, documenting that serum
ferritin was reflective of iron status.
Hemolytic parameters such as reticulocyte count and the
hemolytic component were significantly lower with lower
ferritin levels.
In multivariable analysis these relationships remained
statistically significant (P for MCV and ferritin: 0.003,
P for hemolytic component and ferritin: 0.044) even after
correcting for alpha-thalassemia, which is known to also
lower MCV and hemolysis, and for markers of inflammation
(WBC) and liver disease (ALT), which could increase the
ferritin level regardless of iron stores.
Ferritin was significantly lower in older subjects, probably
as a result of growth-related red cell mass expansion in the
presence of marginal iron stores.
Our results thus suggest that low iron stores are independently
associated with decreased hemolysis.
Low hemolysis is likely to be beneficial in SCD by reducing
hemolysis-related vasculopathy, which in adult SCD patients
predicts an increased risk of pulmonary hypertension, leg
ulcers, priapism, and death.
Whether iron status per se plays a role in the pathogenesis
of SCD vasculopathy is not known.
In non-SCD adults, decreasing iron stores by frequent blood
donation has beneficial effects on endothelial function and
cardiovascular disease even within the normal range for iron
stores.
Hence, lowering iron stores could benefit SCD subjects by
an additional, hemolysis-independent mechanism.
Therapeutic iron depletion is not an option for children
because of their need for adequate iron stores for optimal
physical and neuro-psychological development.
However, carefully controlled studies should be considered to
reduce iron stores and so decrease the hemolytic rate in
adults with SCD.
It may be possible to achieve levels of iron reduction that
lower hemolysis but do not worsen the anemia: in our study
subjects, low iron stores were not associated with increased
anemia and the red cell counts were actually higher with
lower ferritin levels.
Disclosures: Gordeuk: TRF Pharma: Research Funding; Merck:
Research Funding; Biomarin pharmaceutical company:
Research Funding; Novartis: Speakers Bureau.
© 2009 American Society of Hematology