Meta-Biol

• Pathways

The ectonucleoside triphosphate diphosphatase (E-NTPDase family) of ectonucleotidases includes 8 enzymes: NTPDase1 (encoded by the ENTPD1 gene), NTPDase2 (encoded by the ENTPD2 gene), NTPDase3 (encoded by the ENTPD3 gene), NTPDase4 (encoded by the ENTPD4 gene), NTPDase5 (encoded by the ENTPD5 gene), NTPDase6 (encoded by the ENTPD6 gene), NTPDase7 (encoded by the ENTPD7 gene) and NTPDase8 (encoded by the ENTPD8 gene). NTPDases hydrolyze nucleoside triphosphates and nucleoside diphosphates, producing the corresponding nucleoside monophosphates as final products. Different family members show different specificity for particular nucleotides. NTPDases are involved in various biological processes, such as hemostasis, immune response and development of the nervous system.
The catalytic domain of NTPDases is contained within the loop formed by a cluster of apyrase conserved regions (ACRs). All family members require divalent cations, such as calcium (Ca2+) or magnesium (Mg2+) ions, for catalytic activity. The hydrolysis involves a nucleophilic attack of a water molecule on the terminal phosphate of a nucleotide substrate.
All E-NTPDase family members are transmembrane proteins, associated with either plasma membrane (NTPDase1, NTPDase2, NTPDase3 and NTPDase8) or organelle membranes (NTPDase4 and NTPDase7). Two family members, NTPDase5 and NTPDase6, can be secreted into extracellular space following a proteolytic cleavage from the plasma membrane. NTPDases hydrolyze exocytoplasmic nucleotides, thus regulating the availability of ligands for purinergic receptors. Glycosylation and oligomerization are involved in the regulation of NTPDases, but have not been thoroughly studied.

For reviews of the NTPDase family, please refer to Robson et al. 2006 and Zimmermann et al. 2012.

Nucleotides and their derivatives are used for short-term energy storage (ATP, GTP), for intra- and extra-cellular signaling (cAMP; adenosine), as enzyme cofactors (NAD, FAD), and for the synthesis of DNA and RNA. Most dietary nucleotides are consumed by gut flora; the human body's own supply of these molecules is synthesized de novo. Additional metabolic pathways allow the interconversion of nucleotides, the salvage and reutilization of nucleotides released by degradation of DNA and RNA, the catabolism of excess nucleotides, and the transport of these molecules between the cytosol and the nucleus (Rudolph 1994). These pathways are regulated to control the total size of the intracellular nucleotide pool, to balance the relative amounts of individual nucleotides, and to couple the synthesis of deoxyribonucleotides to the onset of DNA replication (S phase of the cell cycle).

These pathways are also of major clinical interest as they are the means by which nucleotide analogues used as anti-viral and anti-tumor drugs are taken up by cells, activated, and catabolized (Weilin and Nordlund 2010). As well, differences in nucleotide metabolic pathways between humans and aplicomplexan parasites like Plasmodium have been exploited to design drugs to attack the latter (Hyde 2007).

The movement of nucleotides and purine and pyrimidine bases across lipid bilayer membranes, mediated by SLC transporters, is annotated as part of the module "transmembrane transport of small molecules".

Metabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as the inactivation and elimination of toxic ones generated endogenously or present in the extracellular environment. The processes of energy metabolism can be classified into two groups according to whether they involve carbohydrate-derived or lipid-derived molecules, and within each group it is useful to distinguish processes that mediate the breakdown and oxidation of these molecules to yield energy from ones that mediate their synthesis and storage as internal energy reserves. Synthetic reactions are conveniently grouped by the chemical nature of the end products, such as nucleotides, amino acids and related molecules, and porphyrins. Detoxification reactions (biological oxidations) are likewise conveniently classified by the chemical nature of the toxin.

At the same time, all of these processes are tightly integrated. Intermediates in reactions of energy generation are starting materials for biosyntheses of amino acids and other compounds, broad-specificity oxidoreductase enzymes can be involved in both detoxification reactions and biosyntheses, and hormone-mediated signaling processes function to coordinate the operation of energy-generating and energy-storing reactions and to couple these to other biosynthetic processes.