Asalvage pathway is apathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. The term often refers tonucleotide salvage in particular, in whichnucleotides (purine andpyrimidine) are synthesized from intermediates in their degradative pathway.
Nucleotide salvage pathways are used to recoverbases andnucleosides that are formed duringdegradation ofRNA andDNA. This is important in some organs because some tissues cannot undergode novo synthesis. The salvaged products can then be converted back into nucleotides. Salvage pathways are targets fordrug development, one family being calledantifolates.[1]
A number of other biologically-important substances, likemethionine andnicotinate, have their own salvage pathways to recycle parts of the molecule.
The nucleotide salvage pathway requires distinct substrates:
Uridine phosphorylase orpyrimidine-nucleoside phosphorylase substitutes the anomeric-carbon-bonded phosphate of ribose 1-phosphate for the free baseuracil, forming the nucleosideuridine.Uridine kinase (akauridine–cytidine kinase) can thenphosphorylate the 5’-carbon of this nucleoside intouridine monophosphate (UMP). UMP/CMP kinase (EC2.7.4.14) can phosphorylate UMP intouridine diphosphate, whichnucleoside diphosphate kinase can phosphorylate intouridine triphosphate.
Thymidine phosphorylase or pyrimidine-nucleoside phosphorylase adds 2-deoxy-alpha-D-ribose 1-phosphate tothymine, with thymine bonding at the anomeric carbon of the deoxyribose, forming the deoxynucleosidethymidine.Thymidine kinase can then phosphorylate the 5’-carbon of this compound intothymidine monophosphate (TMP).Thymidylate kinase can phosphorylate TMP intothymidine diphosphate, which nucleoside diphosphate kinase can phosphorylate intothymidine triphosphate.
The nucleosidescytidine anddeoxycytidine can be salvaged along the uracil pathway bycytidine deaminase, which converts them to uridine anddeoxyuridine, respectively. Alternatively, uridine–cytidine kinase can phosphorylate them intocytidine monophosphate (CMP) ordeoxycytidine monophosphate (dCMP). UMP/CMP kinase can phosphorylate (d)CMP intocytidine diphosphate ordeoxycytidine diphosphate, which nucleoside diphosphate kinase can phosphorylate intocytidine triphosphate ordeoxycytidine triphosphate.
Phosphoribosyltransferases add activated ribose-5-phosphate (Phosphoribosyl pyrophosphate, PRPP) to bases, creating nucleoside monophosphates. There are two types of phosphoribosyltransferases: adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT). HGPRT is an important enzyme in Purine pathway metabolism and[2] its deficiency is implicated inLesch–Nyhan syndrome.
| Nucleobase | Enzyme | Nucleotide |
|---|---|---|
| hypoxanthine | hypoxanthine/guanine phosphoribosyl transferase (HGPRT) | IMP |
| guanine | hypoxanthine/guanine phosphoribosyl transferase (HGPRT) | GMP |
| adenine | adenine phosphoribosyltransferase (APRT) | AMP |
Tetrahydrofolic acid and its derivatives are produced by salvage pathways from GTP.[1]
L-methionine salvage is the pathway that regeneratesmethionine from its downstream products. A version of the pathway usesmethylthioadenosine (MTA), forming the so-called MTA cycle with its synthesizing reaction. This sulphur-recycling action is found in humans, and seems to be universal among aerobic life.[3][4]
Nicotinate salvage is the process of regeneratingnicotinamide adenine dinucleotide fromnicotinic acid. This pathway is important for controlling the level ofoxidative stress in cells. The human geneNAPRT encodes the main enzyme in the pathway.[5] Cancer cells, which have increased NAD requirements, tend to upregulate the pathway.[6]
Salvage pathways also exist forceramide,cobalamin,cell wall components, andtetrahydrobiopterin in various organisms.