Page 136 - The Biochemistry of Inorganic Polyphosphates

WU095/Kulaev
WU095-07
Functions of polyphosphate and polyphosphate-dependent enzymes
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The nuclei of animal cells contain PolyPs (Griffin et al., 1965; Mansurova et al., 1975a;
Penniall and Griffin, 1984; Kumble and Kornberg, 1995). In the nuclei of rat liver, PolyP is
related to the fraction of non-histone proteins (Kulaev and Vagabov, 1983; Offenbacher and
Kline, 1984). PolyP may interact with DNA-histone binding in chromatin and this binding
has been shown to inhibit the activity of some nuclear enzymes, including topoisomerases
(Schr¨oder et al., 1999). These data support the idea that PolyPs are involved in the regulation
of chromatine functioning in animals.
One example of the probable regulatory function of PolyPs in animals is the ability
of these polymers when added to culture media to enhance the proliferation of normal
human fibroblast cells. PolyPs also enhanced the mitogenic activities of acidic fibroblast
growth factor (FGF-1) and basic fibroblast growth factor (FGF-2). A physical interaction
between PolyP and FGF-2 was observed, which stabilized this protein. Furthermore, PolyPs
facilitated the FGF-2 binding to its cell surface receptors (Shiba et al., 2003).
PolyPs stimulated mammalian TOR, a kinase involved in the proliferation of mammary
cancer cells (Wang et al., 2003).
The functions of PolyPs associated with their anionic nature were also retained. P i trans-
ported into the lysosomes of human fibroblasts incorporates high-polymer PolyPs synthe-
sized in these organelles (Pisoni and Lindley, 1992). Lysosomes are a storage compartment
for bioactive amines, and PolyPs might be able to form complexes with these compounds.
A similar process of PolyP synthesis was also observed in granulocytes (Cowling and
Birnboim, 1994).
Complexes of PolyP and PHB, similar to those in bacteria, were found in the membranes
of the endoplasmic reticulum and mitochondria of animal cells (Reusch, 1989, 1999a,
2000; Reusch and Sadoff, 1988), which suggests their participation in the processes of
transmembrane transfer. The most intriguing report was that the Ca–ATPase purified from
humanerythrocytescontainsPolyPsandPHBsandthattheplasmamembraneCa –ATPase
2+
may function as a polyphosphate kinase; this exhibits ATP–polyphosphate transferase and
polyphosphate–ADP transferase activities. These findings suggest a novel supramolecular
structure for the functional Ca –ATPase and a new mechanism of ‘uphill’ Ca 2+ extrusion
2+
coupled with ATP hydrolysis (Reusch et al., 1997).
It was revealed that PolyPs possess antiviral activity by preventing the binding of a virus
to a cell (Lorenz et al., 1997c). Human blood plasma, serum, peripheral blood mononuclear
cells and erythrocytes contain significant amounts of PolyPs (ranging from 53 to 116 µMin
terms of phosphate residues). At higher concentrations, the PolyPs may exhibit cytoprotec-
tive and antiviral activities. Sodium tetrapolyphosphate and longer polymers, with average
chain lengths of 15, 34 and 91 phosphate residues, significantly inhibited the infection of
cells by the human immunodeficiency virus type 1 (HIV-1), in vitro at concentrations higher
−1
than or equal to 33.3 µgml , whereas PolyP 3 was ineffective. Over the tested concentration
range, these compounds had no effect on cell growth. PolyPs with average chain lengths of
15 and 34 P i residues, but not PolyP 3 and PolyP 4 , also inhibited HIV-1-induced syncytium
−1
formation at a concentration of 160 µgml . The results obtained in the syncytium as-
say and cell–virus binding experiments indicate that the anti-HIV effect of these non-toxic
polyanions may be caused by the binding of these compounds to both the host cell surface
and the virus, thereby inhibiting attachment of the virus (Lorenz et al., 1997c). Significant
amounts of PolyPs and of exopolyphosphatase activity were detected in human-mandibule-
derived osteoblast-like cells. The amounts of both soluble and insoluble long-chain PolyPs
in unstimulated osteoblast-like cells were higher than in human gingival cells, erythrocytes,