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~WRL2521 Revised

~WRL2521 Revised

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Published by Newdeersci
Interactions between inorganic ions and cell surface polysacchrides seems to provide a code system which interfaces organisms with their environments. Human health and disease is suggested to be influenced to a major extent by these kinds of interactions e.g. when they occur between the metallome and the heparanome
Interactions between inorganic ions and cell surface polysacchrides seems to provide a code system which interfaces organisms with their environments. Human health and disease is suggested to be influenced to a major extent by these kinds of interactions e.g. when they occur between the metallome and the heparanome

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Published by: Newdeersci on Oct 04, 2010
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02/02/2013

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20/4/05 Modified 18/5/08 Reformatted 25/5/09. Plus additional Figure for submission to
e.g 
. N. P.
The Relevance to Metallomics of the Binding of Metal Ions to Heparin/Heparan Sulphate.
 Heparin may provide a high capacity multi-element binding matrix of especial relevance to biological metallomicresearch.
The heparanome and metallome are suggested to interact and modulate the activity of a range of biological processes in animals
David Grant
(A hypothesis compiled from research carried out at Marischal College, University of Aberdeen*re-copied in modified form from a note written 4/2/05)
Summary
It is suggested that the heparanome and the metallome cross react
in vivo.
Heparins (and putatively heparan sulphates) like alginates, unless specially purified, are apparentlychemically so constituted to as to retain the full range of multi-inorganic elements which occur inseawater.Of especial interest is the putative requirement for Ca
2+
, Mg
2+
and possibly also Mn
2+
and Cu
2+
ions for thelinkage of heparan sulphate anionic patterns to target proteins and the requirements for Cu
2+
(and Cu
+
)andZn
2+
ions for the nitrosative generation of heparan sulphate oligosaccharides required for inter- and intra-cellular signalling.
Introduction
The metallome, a scientific field which was originally suggested by R.J.P. Williams (
cf 
. 1) butlater redefined by H. Haraguchi (2) to emphasize the inter-relationships between the multielement profilesof biological and geological matrices,
e.g 
., between seawater and human blood serum.Human hair and nails (
cf 
. 3) it should be noted, are also common examples of apparent Haraguchi-multi-element-matrices.It should be noted that while it is commonly assumed (
e.g 
. as in the recent review of metallomics byMounicou
et al 
. (1)) that the biological relevance of metallomics is restricted entirely to the provision of theessential metal ions required for the generation of active sites in metallo-proteins, it can rationally besuggested that the concept of the metallome could also be of value to enable a fuller understanding of mechanisms by which polysaccharides interact with other types of bio-molecules. This could especially
 
apply to those highly anionic polysaccharides (
e.g 
. alginate (4) and heparin (5)) which apparently existintheir native states as well-defined Haraguchi-type multi-inorganic element matrices. This idea could also beapplicable to the heparin-like segments which occur in the heparan sulphate side chains which are the basisof the heparanome (6) (
cf 
. 7) which is thought to play major signalling roles throughout animal biochemistry (8-10) including by its ability to behave as a high capacity flexible information holding and processing system.The mechanism by which this heparanome information code functions could, at least partly, it is now argued, be dependent on the provision of inorganic elements by the metallome.This idea is supported by
in vitro
studies of the binding of metal ions (11, 12) and inorganic anions (13)to heparin and heparan sulphate, the roles of metal ions in heparin and heparan sulphate biochemicalsignalling (14) and the evidence that high affinity binding between multivalent metal ion labels andheparan sulphate occurs
e.g 
. during
in vivo
scintigraphic tissue imaging (15).A further role of metal ions seems to be the regulation of nitrosative and enzymic scission processes (16)which can generate messenger heparan sulphate oligosaccharides which are now believed to exert key biochemical signalling actions.
The inorganic constitution of unpurified heparin suggests that heparin/heparan sulphate will exist in vivoas a metallomic matrix
The amounts of the numerous kinds of inorganic elements present in several samples of pharmaceuticalheparin showed an approximate correlation with the amounts of such elements present in human bloodserum or seawater (as illustrated by Fig. 1); this circumstance equally seems to apply to heparins fromdifferent manufacturers, and following the conventional partial single counterion enrichment of heparinachieved by the percolation of multi-inorganic element substituted heparin solutions through a selectedsingle counter-ion substituted forms of ion exchange resin columns..
 
Since the existence of the above type of seawater-like multi-inorganic-element profile has also been previously fairly well established to occur with the anionic polysaccharides present at the cell walls of for marine algae (4), the origin of the metallomic range of inorganic elements in heparin is therefore probablynot, as was formerly supposed, from contamination arising during industrial work-up, but is more likelytohave been determined by the
in vivo
sequestration of inorganic elements from the seawater-like multi-inorganic salt solutions present in the originating animal biological fluids in a similar manner to how themarine alginates acquire their bound multi-inorganic ions and inorganic particles by the sequestration of these moieties from seawater. NMR studies suggested that heparin and related polysaccharides possess a complex inorganic ion bindingsystem which allows inorganic ions to be held both in rapid site change locations, at more securelocationsand also to occur 
e.g 
., in phase separated locations (
cf 
. 12).The relative amounts of the different types of inorganic elements which have become established to

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