sulphate probably exists
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 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 (
. 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.
. 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
., 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 (
) 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
.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
ions to permit endostatin - heparansulphate binding was discovered (10b). Whilst binding to Zn
will normally occur
, this bindingwas found to be it is abolished
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.
, 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
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
are required for
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