Welcome to Scribd, the world's digital library. Read, publish, and share books and documents. See more
Download
Standard view
Full view
of .
Look up keyword
Like this
1Activity
0 of .
Results for:
No results containing your search query
P. 1
~WRL3217 contiued modif

~WRL3217 contiued modif

Ratings: (0)|Views: 10|Likes:
Published by Newdeersci
The literature reports of the key roles of inorganic cofactors in heparin/heparan sugnaling suggest
that the heparanome functions
in conjunction with the metallome
The literature reports of the key roles of inorganic cofactors in heparin/heparan sugnaling suggest
that the heparanome functions
in conjunction with the metallome

More info:

Published by: Newdeersci on Jul 12, 2010
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as DOC, PDF, TXT or read online from Scribd
See more
See less

02/11/2013

pdf

text

original

 
20/4/05 Modified 18/5/08; 20/5/09
The Relevance to Metallomics of the Binding of Metal Ions to Heparin/Heparan Sulphate.
Heparin may provide a high capacity multilelement binding matrix of especial relevance to biological metallomic research.
The heparanome and metallome are suggested to interact and modulate the activity of a range of fundamental biological processes in animals.David Grant
*(A hypothesis compiled from research carried out at Marischal College, University of Aberdeen*re-copied from a note written 4/2/05 at Turriff AB53)
Summary
The metallome, a new scientific field designated by H. Haraguchi which concerns,
inter alia
therelationships between the multielement profiles of biological and geological matrices, is now suggestedto be highly relevant to the heparanome, the system of heparin/heparan sulphate polysaccharides whichoccur in multicellular animal and which may provide, in addition to the modulation of many proteinactivities, a wideranging system of homeostasis for metal ions and H
+
. The heparanome and themetallome may cross react
in vivo
Introduction
Recent discussion of the relevance of the large number (
ca.
80) of elements routinely detected by massspectroscopic analysis in biological matrices has led H. Haraguchi (1) to elaborate some of the earlier ideas of R.J.P. Williams, and to initiate a new scientific field dealing with the occurrence and relevanceof multielement matrices for which the term “metallomics” has been suggested. Implicit in the concept of metallomics is the possible significance of connections between geology, inorganic chemistry and biology The metallome was suggested by Haraguchi to apply to biology principally for the provision of metal ions required to generate active sites in proteins (1). It is now suggested that a similar fundamentalrequirement of metal ions as essential cofactors for polysaccharides is also of relevance. Metal ions areknown to occur naturally in anionic polysaccharides (1a,b,c) including heparin (1d) which sequestersCu
2+
Ca
2+
and Zn
2+
(1g) in a physiologically relevant manner. This phenomenon could be criticallyrelevant to the activity of the “heparanome”** (2) (the heparin/heparan sulphate and (putatively) metalion dependent signalling system in animal biology (2-9)). Heparin may contain a surprisingly largeamounts of the least abundant of the full range of the ultratrace non-physiological elements (1d) whichare also now known to consistently occur in biological fluids including blood serum (1). While it is nowfairly well established that Cu
2+
, Ca
2+
and Zn
2+
are essentially required cofactors for various heparanome-related protein control mechanisms (10), (10b) (some examples of which are listed in Table I), thevarious ultratrace inorganic ions which occur in biological fluids (1) but which currently have no known physiological function, might conceivably also be involved in heparin/heparan sulphate signalling or itsanthropogenic perturbation.
 
Medical Use of Metal Ion Binding to Heparin/Heparan Sulphate
Binding of Eu
3+
(11) can be used for heparin assay in blood samples.Pathological lesions can be imaged (12) by an altered binding of metal ion radiolabels such as 67Ga.Similar use of 111In and 99Tc labelled heparin (13), however, seemed to be less effective.67Ga is believed to bind especially strongly to the heparan sulphates which occur at all adherent cellsurfaces but are subject to structural alteration as a consequence of pathological situations
e.g 
. cellular oncogenic transformation (14).
 In vitro
studies (12a) confirmed that radioimaging by metal ions is facilitated by an alteration in theanionic density of heparan sulphates associated with pathological lesions (rather than,
e.g 
., transferrin),this being confirmed by an
in vitro
study which confirmed that a wide range of physiologically relevantmetal ions bind to heparan sulphate (11e). These findings also tend support the notion that heparan
 
sulphate probably exists
in vivo
as a form of specific metallomic matrix. 
Participation of Metal Ions in Heparin/Heparan Sulphate Signalling
.Heparin/heparan sulphate, which contains a linear encoded information system, is produced by an as yetnot fully understood biosynthesis in the Golgi apparatus, which includes epimerisation, deacetylation andsulphation stages (2-9) but also is subjected to a postsynthetic modification by both enzymic (15) andnon-enzymic (16) (16a) (16b) pathways which are apparently used for the creation and transmission of encoded information in the form of anionic polysaccharides. These anionic polysaccharides are nowsuggested always to occur 
in vivo
in the form of (multiple) metal ion complexes. This information processing system apparently also includes possibly complex metal ion-dependent inputs from enzymicand non-enzymic scission by redox metal ion generated radicals as well as by specific redox metal iondependent deaminative cleavage reactions (17).The postsynthetic coding alteration of heparin/heparan is not restricted, as is DNA, by a requirement to preserve genetic information, so that while the entire signal in heparan sulphate chains is believed to beof physiological significance (
e.g 
. as a sort of biological postcode for defining particular cellular typesandlocations the details of which have not yet been established owing to the lack of sequencing methods asgood as those available for nucleic acids) the heparan sulphate chains are normally utilised after beingspecifically modified to generate fragments containing information packets designed to be read at distantsites (18-20).
Metal Ions Can Link Heparin/Heparan Sulphate Domains to Proteins
A effect of the binding to heparin/heparan of (non-redox) metal ions may be to assist heparan sulphate- protein binding which at least in some cases, has an absolute requirement for specific divalent metal ions,which are apparently needed to create a correct linkage between the two types of polymers to facilitatenormal heparin/heparan sulphate biochemical control processes.
Cf 
. the anticoagulant heparin/heparan sulphate antithrombin (III) binding sequence which is the major mammalian bloodanticoagulant mechanism which operates in conjunction with the action of divalent metal ions which similarly can affect growthfactor receptor activation by a process which could further be relevant to the toxic actions of 
e.g 
., barium ions in the aetiology of degenerative diseases in which abnormal growth factor activities are apparent.
Table I collects some of the reported evidence for an absolute requirement for the presence of specificdivalent metal ions (
e.g 
. Ca
2+
or Zn
2+
) putatively required to generate the required polysaccharideconformations in order to achieve the correct interactions with their target proteins.These actions, it may be supposed, may be perturbable by such toxic ions as Pb
2+
, Cd
2+
and Ba
2+
.It must be emphasised that although metal ions are known (Table I) to have critical roles in themodulation of heparin/heparan sulphate - protein interactions, this may only be discovered fortuitously,as exemplified by how the requirement for the presence of Zn
2+
ions to permit endostatin - heparansulphate binding was discovered (10b). Whilst binding to Zn
2+
will normally occur 
in vivo
, this bindingwas found to be it is abolished
in vitro
unless Zn
2+
ions, evidently removed during column polysaccharidegel purification processes, were reintroduced. Required metal ions can evidently also bind strongly to the polysaccharides used for usual chromatographic separations which may therefore be the unexpectedsource of experimental errors.
 In vivo
, sufficient metal ions for facilitation of the correct protein-heparan sulphate interactions willnormally be present in common physiological fluids but may be absent in sufficient amounts after column gel fractionations or in physiological saline solutions prepared by use of chemically pure sodiumchloride.A direct observation of Ca
2+
ions linking annexin-V and heparin is shown by the X-ray structure of aheparin oligosaccharide annexin-V complex (10c). Heparin/heparan sulphate and Ca
2+
are required for 
invivo
structure building of functionally active annexin-V aggregates at the plasma membrane.The structure of fibroblast growth factor receptor dimer (10e) shows a similar divalent cation dependent
 
interlinking of heparan sulphate to protein.
The Role of Heparin/Heparan in Controlled Assembly/Disassemblyof Solid Phases
The assembly, disassembly and inhibition of crystalline and semi-amorphous substance formation isstrongly affected by the presence of anionic polysaccharides, which includes the important function of heparin/heparan sulphate for the inhibition of pathological calcification (21) and also for an apparentantioxidant mechanism involving the removal of Cu
2+
(22), Fe
2+
(23) and Fe
3+
(24) ions from the solution phase including by the binding of these ions to heparin/heparan sulphate, and their assembly into redox-inert aggregates (25) similarly to how chitosan and hyaluronan have recently been reported (26) toachieve a similar antioxidant protection. Heparin may bind paramagnetic ions in aggregated insolubleforms (26a).
Discussion
Polysaccharides, occurring abundantly throughout biota, characteristically bind to and may,
in vivo,
naturally contain a wide range of both nutrient and toxic elements present in amounts which shows anapproximate correlation with the amounts of such elements in blood serum and seawater (1).This circumstance seems relevant,
inter alia
, to a full definition of the scope of metallomics (1) a new branch of biometal science, which aims to compare and evaluate the relevance of various multielement profiles throughout biology and geology.Electrostatic theory (
e.g 
. that of Manning) predicts that polyelectrolytes will bind oppositely chargedcounterions equally for equally charged counterions. In depth studies of the mechanism of binding of counterions to heparin (26a) dis not, however, support the Manning electrostatic binding theory, despitethe similarity of the strength of binding found to be achieved of many similarly charged cations toheparin which had been predicted by this theory. The Manning electrostatic attraction theory cannotaccount for the well-established the ability of the ultraanionic heparin anions to strongly to associatedwith SO
42-
anions (27). The non-electrostatic binding activity of polyol groups within all polysaccharides may, however, be responsible for this. Such a general mode of binding by all polysaccharides evidently become modulated by additional electrostatic fields present in anionic polysaccharides exemplified by heparin/heparan sulphate. These formally ultra-anionic polysacchairdesalso show great structural diversity (to which inorganic ions it is now suggested also contribute). Thisflexible diversity apparently enables these molecules to perform a wide range of signalling and controlfunctions in animal biochemistry. It is therefore predicted that the precise physical chemical andultrastructural details of the counterion profile (and its ability to engage in variable rapid site exchange(
cf 
. 28)) and the possible perturbation of this by anthropogenic input, could be highly relevant to the
invivo
molecular (/supramolecular) structure forming and physiological activities of these polysaccharides.Specific metal ions (
e.g 
. Ca
2+
) have previously been reported to be absolutely required for severalhepain/heparan sulphate protein binding and regulation functions, some examples of these effects beinglisted in Table I. Inorganic cations and anions have also been reported to modulate heparan sulphate primarly biosynthesis as exemplified in Table II and specific cations may be are required for  postsynthetic structural modification (
cf.
Table I).
Table I
 Examples of facilitation by divalent cations of the binding of heparin/heparanto proteins.

You're Reading a Free Preview

Download
scribd
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->