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Heparin-Like Polysaccharides are Multi-Element Sequesters and
Potential Metallomic ReservoirsComment ontheHaraguchi Metallomics
Hypothesis. Possible Key Roles of Polysaccharides and Silicon.From
David Grant* MRSC Turriff-New Deer AB 53 6SX, U.K.Haraguchi1
proposed a new branch of science, metallomics, to integrate the
research fields related to
biometals especially via the systematic study of the now widely
available multi-element profiles ofbiologically relevant matrices.
It is now suggested that polysaccharides could provide a
majorextracellular system of multi-element reservoir functions
relevant to this hypothesis. In contrast to the
high affinities for specific metal ions associated with the
enzyme activating roles of metals in proteins,polysaccharides
commonly bind metal ions at a range of modest affinities which
nevertheless enablesthem to simultaneously sequester the full range
of physiologically relevant inorganic elements and also to
bio-concentrate the less-abundant inorganic elements which occur
in natural aqueous solutions. Well-defined examples of
polysaccharide organometallic complexes occur in agarophytes2 and
in animal mastcell derived heparin and therefore putatively also in
similar structured heparan sulphate segments whichact assmart
anionic density-related encoded system managers3, 4 which exist at
adherent cell surfaces andextracellular matrices in all animals.
For aquatic invertebrates the amounts of such heparin-like
polysaccharides seemed5 to be determined by exact mathematical
relationships with the habitat salinitieswhich could suggest a
critical need to form specific inorganic salt heparin-like
polysaccharide complexeswhich are perhaps similar in composition to
the Haraguchi-type7 multi-element matrix compositionswhich are
characteristic features of the inorganic biochemistry of heparin6
(cf. Table 1, A and Fig.1 for
Na heparin and Table 1, B for a Tl heparin obtained from the Na
heparin of column A 7b).The reported multi-inorganic elements
contents of heparins used in blood collection tubes 7c
alsoindictated that these commercially used heparin preparation are
of a similar inorganic composition to theTl heparin listed in Table
1, Column B.Studies of single counterion enrichment by percolation
use of a cationic ion exchange resin suggestedthatmost elements
(excepting, e.g., cerium and lead ) are easily replaceable by this
procedure. This furtherindicates that in vivo heparin-like
molecules will engage in similar ion-exchange and related
transportactivities.Approximate interrelationships exist between
the elemental compositions of heparin and human bloodserum and
scalp hair,8, cf., Table 1, columns A and C.A biological
fingerprint is revealed by inorganic element log-log plots (cf. the
relatedness which isapparent between modern seawater and human
blood serum1 and between modern seawater and Naheparin suggested by
Fig. 1.
Similar approximate exponential inter-relationship can also be
demonstrated to exist between theinorganic elemental compositions
of marine alginates, heparin, seawater and geological fulvates.
The marked reduction in bound Si which occurs during the ion
exchange column percolation replacementof cations from heparin
suggests that Si is mostly linked to heparin via the most abundant
counter-cations
present. This behaviour could be relevant to the elucidation of
the mystery of why Si is an essentialnutrient for animals. This is
now suggested to be because Si may permit selective heparan
sulphate
protein interactions9e.g. in an analogous manner to those
promoted by other essential inorganic ions.This includesthe
essential requirement for divalent cations for the modulation of
fibroblast growth factor receptoractivation during growth factor
signalling10. Metallomic reservoirs, by controlling the
availability of theinorganic cofactors required for such processes,
could exert a pivotal influence.The proposed metallomic role of Si
in biological systems could ultimately also derive from the
uniqueinorganic chemistry of silicic acid and how this may provide
for the system of homeostasis of inorganic
ion concentrations in the sea. The evolution of biota may have
depended on the ease with which (pre-biotically relevant)
self-assembly of silicic acid could occur under the slightly
alkaline conditions of thesea. This aggregation process is known to
produce cell-like colloidal particles similar to the silica
particles which are able to replicate in a quasi-biological
manner as can be observed 11 during theindustrial batch production
of silica sols on a heel retained from a previous batch by a
process whichresembles seeded crystallisation.The ultimate reason
why the multi-inorganic elemental composition of the sea is
replicated in theextracellular fluids of animals could be that
there is some fundamental need to retain the originalinorganic Si-
centered system (e.g. related to water activity fine-tuning) which
later came to be provided
by the kinds of Si-containing polysaccharides which probably
have existed since the time of the first
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evolution of multicellular animals in the sea.*From the authors
researches conducted at Marischal College, Aberdeen, U.K., with the
encouragement of W.F. Long and F.B. Williamson.
References
1 H. Haraguchi,J. Anal. At. Spectrom., 2004, 19, 5-142 K. Truus
et al.,Proc. Eston. Acad. Sci., Chem ., 2001, 50, 95-103;
forAscophylum nodosum see
http://www/alginure.co.uk/ascophylum-nodosum.html;forEcklonia
maxima seehttp://www.gaiaresearch.co.za/kelp.htmlcf., T.A. David et
al.,Appl. Biochem. Biotechnol., 2003, 110, 75-909
A. Wassermann,Ann. Bot., N.S., 1949, 13, (49) 81-88W.A.P. Black
and R.L. Mitchell,J. Mar. Biol. Assoc., UK, 1952, 30 (3)
575-584
3 Heparan sulphates contain heparin-like segments which are an
important part of the information-encoded system which allowsthe
heparanome to act as a high-ranking system manger in animal
biology. The ubiquitous close association of metallomicmatrices
with these segments must indicate that such inorganic elements
contribute to the modus operandi of this informationrelay
system.
Cf., J. Turnbull et al., Trends Cell Biol., 2001, 11, 75-82;
cf., M. Bernfield, et al.,Ann. Rev. Biochem., 1999, 68,
729-777;P.W. Parket al.,J. Biol. Chem., 2000, 275, 29923-29926T.R.
Rudd et al., Glycobiology, 2007, 17 (9) 983-993; Carbohydr Res.
2008, 343, 2184-2193.
4 S Kojima, et al., Eur J Nucl Med., 1983, 8, 52-59; ibid.,
1984, 9, 51-565 H.B. Naderet al. Comp. Biochem. Physiol.B,1983,
76B, 433-4366 D. Grant et al.,Biochem. J., 1991, 275, 193-197;
ibid., 1992, 287, 849-853; ibid., 1992, 282,601-604; ibid., 1992,
283,
243-246; ibid., 1992, 285,477-480; Biochem. Soc. Trans., 1991,
18, 1281-1283; ibid., 1991, 19, 390-395S; ibid, 1996, 24,203-204S;
D.L. Rabenstein et al., Carbohydr. Res., 1995, 278, 239-256; S.A.
Katz,Amer. Biotechnology Lab., 1984, 2, 24-30
7 a D. Grant, Chemistry Preprint Archive, 2000 Oct., 94-104;
(http://preprint.chemweb.com/biochem/0010002)b D Grant, et
al.Biochem J., 1987, 244, 143-1496; C.F. Moffat Synthesis,
Characterisation and Application of ChemicallyModified Heparins
Ph.D. Thesis University of Aberdeen, Department of Biochemistry,
1987c ALS at
http://www.analytica.se/hem20045/pdf/blood_collection_tubes.eng.pdfThis
report lists inter alia the full seawater range of multi-inorganic
elements which can be leached from lithium and sodium heparinized
blood vessel tubes. The heparins in these tubes is
indicated to be single-pass ion exchanged cleaned-up forms of
Haraguchi-type multi-inorganic element composition (similar to the
heparin listed in Table I column B) and t hat
purified heparin retains typically much greater (ca. x 100)
amounts of inorganic element impurities per mole binding site than
does EDTA which is also used as an anticoagulant in blood
collection tubes.
8 a V.N Senofonte and S Caroli,J.Trace Elem. Med. Biol., 2000,
14, 6-13;b I. Rodushkin and M.D. Axelsson,Sci TotalEnviron., 2000,
250, 83-100; c I. Rodushkin and M.D. Axelsson, ibid., 2000,262,
21-36; d cf.http://www.analytica.se/hem2001/human/research.asp;
http://www.doctorsdata.com/docs/pfd/hair.pdfcf., D.A. Bass et
al.,Altern. Med. Rev., 2001, 6, 472-481 and A.R. Bleise et al.
Analytical Quality Control Services, (HairElements Reference
Sheet), International Atomic Energy Agency,
A-1400,Vienna,Austria
9 E.M. Carlisle, Sci. Tot. Environ., 1988, 73, 95-106; cf. M.F.
McCarty Med Hypoth. 1997, 49 175-176; R.K. Iler, p.762 inThe
Chemistry of Silica,Wiley, New York, 1979
10 M. Kan et al.,J. Biol. Chem., 1996, 271, 26143-261483; cf.,
M. Purdey, Med. Hypoth., 2004, 62, 746-754Rudd et al., DATA
11 D. Grant W.F. Long and F.B. Williamson Med. Hypoth. 1992, 38,
46-4812 N.W. AlcockSerum versus plasma for trace metal analysis,
Elem. Metab. Man, Anim., Proc. Int. Symp. 4th 1981 (Pub 1982),
eds. J.M. Gawthorne, J.M.C. Howell, C.L. White, p. 678-680;
Springer, Berlin; Chem. Abs., 96, 213646f c;
G.F. Harrison and A. Sutton,Nature, 1963 (4869) 809; H.J.M.
Bowen in TraceElements in Biochemistry Academic PressLondon, 1966,
p.63
Table 1 Comparison of The Elemental Contents (mg/kg) of Heparins
& Human Scalp Hair Native Heparin Tl+ Heparin Human
Scalp HairA B C A/C
(a) (s) (b) (c)Si 5900 100 510(s) n.d. 12P 440 30 195(a) 2.3
2.6B
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