Meta-Biol

• Pathways

The pyrimidine orotate (orotic acid) is synthesized in a sequence of four reactions, deriving its atoms from glutamine, bicarbonate, and aspartate. A single multifunctional cytosolic enzyme catalyzes the first three of these reactions, while the last one is catalyzed by an enzyme associated with the inner mitochondrial membrane. In two further reactions, catalyzed by a bifunctional cytosolic enzyme, orotate reacts with 1-phosphoribosyl 5-pyrophosphate (PRPP) to yield orotidine 5'-monophosphate, which is decarboxylated to yield uridine 5'-monophosphate (UMP). While several individual reactions in this pathway are reversible, other irreversible reactions drive the pathway in the direction of UMP biosynthesis in the normal cell. All reactions are thus annotated here only in the forward direction.

This pathway has been most extensively analyzed at the genetic and biochemical level in hamster cell lines. All three enzymes have also been purified from human sources, however, and the key features of these reactions have been confirmed from studies of this human material (Jones 1980; Webster et al. 2001).

All other pyrimidines are synthesized from UMP. The reactions annotaed here, catalyzed by dCMP deaminase and dUTP diphosphatase yield dUMP, which in turn is converted to TMP by thymidylate synthase.

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.