Nucleotide Pyrophosphatase

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Introductions

Nucleotide pyrophosphatase is an enzyme that catalyzes the reaction to cut the nucleotide pyrophosphate bond of NAD+, NADP+, FAD, ATP, ADP, thiamin diphosphate, etc. It has no effect on inorganic pyrophosphate and phosphate monoester. Widely found in living organisms.

Figure 1. Net reaction scheme for Nucleotide Pyrophosphatase/Phosphodiesterase.

Structure and Function of Nucleotide Pyrophosphatase

Nucleotide pyrophosphatases release nucleoside 5'-monophosphates from nucleotides and their derivatives. They exist both as membrane proteins with extracellular active sites and as soluble proteins in body fluids. The only fully characterized NPPs are the mammalian extracellular enzymes NPP1 (PC-1), NPP2 (autocrine motor factor) and NPP3 (B10; gp130(RB13-6)). These are modular proteins consisting of a short N-terminal intracellular structural domain, a transmembrane structural domain, two growth regulator B-like structural domains, a catalytic structural domain, and a C-terminal nuclease-like structural domain. The catalytic structural domain of NPP is conserved from prokaryotes to mammals and shows significant structural and catalytic similarities with those of other phosphate/sulfonyl ligases, such as alkaline phosphatases.

Nucleotide Pyrophosphatase Family

The NPP family includes seven structurally related isozymes (NPP1-7), which are numbered according to the order they were discovered. Four members of this family are known to hydrolyze nucleotides: NPP1 (PC-1), NPP2 (autocrine motor factor), NPP3 (CD203c), and NPP4. They can hydrolyze a variety of nucleotides, including nucleoside triphosphates, dinucleoside polyphosphates, cyclic (di)nucleotides, and nucleotide sugars, releasing monophosphate nucleosides (e.g., AMP and GMP) as products. In addition, it has been proposed that NPP1 can also hydrolyze ATP to ADP and monophosphate (P i ). In contrast to NPP1, 3 and 4, NPP2 has only weak nucleotide metabolic activity and, like some other members of the NPP family, namely NPP6 and NPP7 (alkaline sphingomyelinases), NPP2 preferentially hydrolyzes phosphodiester bonds of phospholipids; therefore, these isoforms can be characterized as phospholipases rather than nucleotidases.

Structure and Function of NPP1

NPP1 is a homodimeric type II transmembrane glycoprotein characterized by an N-terminal transmembrane structural domain, two growth regulator B-like structural domains, a catalytic structural domain, and a C-terminal nuclease-like structural domain. NPP1 contains two growth regulator-B (SMB)-like structural domains, SMB1 and SMB2. Somatomedin-B is a serum peptide that is derived by protein hydrolysis from bilirubin, a serum and extracellular matrix protein involved in cell adhesion.

Figure 2. Structure of the NPP1 dimer, modified from Stefan et al.

Potential Therapeutic Applications of NPP Inhibitors

• Bone mineralization and soft tissue calcification

Age-related increases in NPP1 expression in chondrocytes result in the overproduction of diphosphate (PP i ). Due to the limited enzymatic activity of TNAP, excess diphosphate formation can react with extracellular calcium, resulting in the formation of virtually insoluble calcium diphosphate.

• Type 2 diabetes

The role of NPP in insulin receptor signaling has been reported. Elevated NPP1 expression was found in dermal fibroblast cultures from patients with non-insulin-dependent type 2 diabetes mellitus.

Figure 3. Binding of NPP1 to the insulin receptor, modified from Abate et al.