Human platelet‐derived endothelial cell growth factor is homologous to Escherichia coli thymidine phosphorylase

Monomeric human platelet-derived endothelial cell growth factor (PD-ECGF) is a single-chain protein of relative molecular mass (M,) =45 kDa, which stimulates the growth and chemotaxis of endothelial cells in vitro and possesses angiogenic activity in vivo (Miyazono et al., 1987; Ishikawa et al., 1989). As angiogenesis is central to the pathological conditions of tumor growth, rheumatoid arthritis, diabetic retinopathy, psoriasis, and hemangio-mas, a detailed understanding of the molecular action of PD-ECGF would provide clues to therapeutic strategies for these disease states. Here we report the striking similarity between the primary sequences of PD-ECGF and thymidine phosphor-ylase (TP) from Escherichia coli (Shwartz,l97g). Human TP catalyzes the reversible phosphorolysis of thymidine and other pyrimidine 2'-deoxyribosides, with the exception of 4-amino-substituted compounds and has nucleo-side deoxyribosyl transferase activity. Tp is one of two pyrimidine phosphorylases in the base and nucleoside salvage pathway. Under near-physiological conditions Tp is a homodimer with a molecular mass of I l0 kDa in mammals (Desgranges, l98l) and 90 kDa in E. coti (Shwartz, 1978). Specific inhibitors of TP are considered as potential chemotherapeutics either to reduce clearance of thy-midine and other deoxyuridine analogues presently in use as antineoplastic and antiviral agents or by interfering with the salvage process (Desgranges et al., 1983). The design of such inhibitors may be aided by the 2.8-A-resolution crystal structure of E. coti Tp, which shows Tp to consist of a small helical domain and a larger a/g domain both of which comprise two noncontinuous segments of polypeptide (residues l-65, 163-193 and 80-154, lg7-440, respectively) (Walter et al., 1990). Thymidine and phosphate moieties appear to be bound in a cleft between these two domains. Figure t highlights the sequence similarity between the human PD-ECGF and E coliTP sequences. The similarity extends over all but the N-terminal 32 and the C-terminal 4 residues of PD-ECGF. Human PD-ECGF apparently undergoes posttranslational maturation, whereby l0 and 4 amino acids are removed from the amino and carboxyl termini, respectively (Ishikawa et al., 1989). Mature pD-ECGF has a22-amino acid N-terminal extension with respect to the E. coli TP sequence. The sequences show 4090 identity calculated over the 438 common amino acid positions (see legend to Fig. 1) and are therefore likely to have diverged from a common genetic ancestor and share the same overall tertiary fold (Barton & Sternberg, 1987). Thus, the crystal structure of E. coli TP may be used as a scaffold on which to model …