A salvage pathway is a
pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. The term often refers to nucleotide salvage in particular, in which
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
s (
purine
Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...
and
pyrimidine
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The othe ...
) are synthesized from intermediates in their degradative pathway.
Nucleotide salvage pathways are used to recover
bases and
nucleosides
Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar ( ribose or 2'-deoxyribose) whereas a nucleo ...
that are formed during
degradation of
RNA and
DNA. This is important in some organs because some tissues cannot undergo
de novo synthesis
In chemistry, ''de novo'' synthesis () refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids, as opposed to recycling after partial degradation. For example, nucleotides are not needed in the diet as ...
. The salvaged products can then be converted back into nucleotides. Salvage pathways are targets for drug development, one family being called
antifolates.
[
A number of other biologically-important substances, like ]methionine
Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ...
and nicotinate, have their own salvage pathways to recycle parts of the molecule.
Substrates
The nucleotide salvage pathway requires distinct substrates:
Pyrimidines
Uridine phosphorylase or pyrimidine-nucleoside phosphorylase substitutes the anomeric-carbon-bonded phosphate of ribose 1-phosphate for the free base uracil
Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
, forming the nucleoside uridine. Uridine kinase (aka uridine–cytidine kinase) can then phosphorylate the 5’-carbon of this nucleoside into uridine monophosphate
Uridine monophosphate (UMP), also known as 5′-uridylic acid (conjugate base uridylate), is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside uridine. UMP consists of the phosphate group, th ...
(UMP). UMP/CMP kinase () can phosphorylate UMP into uridine diphosphate
Uridine diphosphate, abbreviated UDP, is a nucleotide diphosphate. It is an ester of pyrophosphoric acid with the nucleoside uridine. UDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase uracil.
UDP is an im ...
, which nucleoside diphosphate kinase can phosphorylate into uridine triphosphate
Uridine-5′-triphosphate (UTP) is a pyrimidine nucleoside triphosphate, consisting of the organic base uracil linked to the 1′ carbon of the ribose sugar, and esterified with tri- phosphoric acid at the 5′ position. Its main role is as sub ...
.
Thymidine phosphorylase or pyrimidine-nucleoside phosphorylase adds 2-deoxy-alpha-D-ribose 1-phosphate to thymine
Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidin ...
, with thymine bonding at the anomeric carbon of the deoxyribose, forming the deoxynucleoside thymidine
Thymidine (symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. ...
. Thymidine kinase can then phosphorylate the 5’-carbon of this compound into thymidine monophosphate (TMP). Thymidylate kinase can phosphorylate TMP into thymidine diphosphate, which nucleoside diphosphate kinase can phosphorylate into thymidine triphosphate.
The nucleosides cytidine
Cytidine (symbol C or Cyd) is a nucleoside molecule that is formed when cytosine is attached to a ribose ring (also known as a ribofuranose) via a β-N1- glycosidic bond. Cytidine is a component of RNA. It is a white water-soluble solid. which ...
and deoxycytidine can be salvaged along the uracil pathway by cytidine deaminase, which converts them to uridine and deoxyuridine
Deoxyuridine (dU) is a compound and a nucleoside.It belongs to a class of compounds known as Pyrimidine 2'-deoxyribonucleosides and closely resembles the chemical composition of uridine but without the presence of the 2' hydroxyl group. Idoxuridin ...
, respectively. Alternatively, uridine–cytidine kinase can phosphorylate them into cytidine monophosphate (CMP) or deoxycytidine monophosphate (dCMP). UMP/CMP kinase can phosphorylate (d)CMP into cytidine diphosphate
Cytidine diphosphate, abbreviated CDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside cytidine. CDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase cytosine.
In ''Bacillus ...
or deoxycytidine diphosphate, which nucleoside diphosphate kinase can phosphorylate into cytidine triphosphate
Cytidine triphosphate (CTP) is a pyrimidine nucleoside triphosphate. CTP, much like ATP, consists of a ribose sugar, and three phosphate groups. The major difference between the two molecules is the base used, which in CTP is cytosine.
CTP is ...
or deoxycytidine triphosphate.
Purines
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 its deficiency is implicated in Lesch–Nyhan syndrome.
The parasite ''Plasmodium falciparum'' relies exclusively on the purine salvage pathway for its purine nucleotide requirements. Thus, enzymes constituting the purine salvage pathway in the parasite are potential targets for drug discovery. 5´nucleotidases catalyze the hydrolysis of purine mononucleotides to their respective nucleosides and phosphate. The nucleosides are taken up in the cell by transporters and are funneled through the salvage pathway. If the nucleoside is adenosine, it is acted upon by adenosine deaminases to convert it into inosine. This metabolite, in turn, is acted upon by purine nucleoside phosphorylase and is converted to hypoxanthine. Hypoxanthine is acted upon by HGXPRT(hypoxanthine guanine xanthine phosphoribosyl transferase) in the parasite to convert the respective nucleobase to its nucleotide monophosphate, respectively (i.e., IMP, GMP or XMP). If it is IMP, this is subsequently acted upon by adenylosuccinate synthase and adenylosuccinate lyase, in a two step process, to convert it into sAMP and AMP, respectively. On the contrary, IMP can also be acted upon by IMP dehydrogenase and GMP synthetase to convert it into GMP.
Folate biosynthesis
Tetrahydrofolic acid and its derivatives are produced by salvage pathways from GTP.
Other salvage pathways
L-methionine salvage is the pathway that regenerates methionine
Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ...
from its downstream products. A version of the pathway uses methylthioadenosine (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.
Nicotinate salvage is the process of regenerating nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...
from nicotinic acid
Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. It can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a varie ...
. This pathway is important for controlling the level of oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
in cells. The human gene NAPRT encodes the main enzyme in the pathway. Cancer cells, which have increased NAD requirements, tend to upregulate the pathway.
Salvage pathways also exist for ceramide, cobalamin
Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. ...
, cell wall
A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mec ...
components, and tetrahydrobiopterin in various organisms.
References
See also
{{Nucleotide metabolism
Nucleotides