In
enzymology
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
, a dihydropyrimidine dehydrogenase (NADP+) () is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that
catalyzes
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the
chemical reaction
A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
:5,6-dihydrouracil + NADP
+ uracil + NADPH + H
+
Thus, the two
substrates of this enzyme are
5,6-dihydrouracil
Dihydrouracil is an intermediate in the catabolism of uracil. It is the base present in the nucleoside dihydrouridine
Dihydrouridine (abbreviated as D, DHU, or UH2) is a pyrimidine nucleoside which is the result of adding two hydrogen atoms to ...
and
NADP+, whereas its 3
products
Product may refer to:
Business
* Product (business), an item that serves as a solution to a specific consumer problem.
* Product (project management), a deliverable or set of deliverables that contribute to a business solution
Mathematics
* Produ ...
are
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 by ...
,
NADPH
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
, and
H+.
In humans the enzyme is encoded by the ''DPYD''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
It is the initial and rate-limiting step in pyrimidine catabolism. It catalyzes the reduction of
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 by ...
and
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 pyrimidine nu ...
.
It is also involved in the degradation of the chemotherapeutic drugs
5-fluorouracil
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancrea ...
and
tegafur
Tegafur is a chemotherapeutic prodrug of 5-fluorouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU.
It was patented in 1967 and approved for medical use in ...
.
It also participates in
beta-alanine metabolism and
pantothenate and coa biosynthesis
Pantothenic acid, also called vitamin B5 is a water-soluble B vitamin and therefore an essential nutrient. All animals require pantothenic acid in order to synthesize coenzyme A (CoA) – essential for fatty acid metabolism – as well as to, ...
.
Terminology
The
systematic name A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature.
A semisystematic name or semitrivial ...
of this enzyme class is 5,6-dihydrouracil:NADP+ 5-oxidoreductase.
Other names in common use include:
* dihydrothymine dehydrogenase
*dihydrouracil dehydrogenase (NADP+)
*4,5-dihydrothymine: oxidoreductase
*DPD
*DHPDH
*dehydrogenase, dihydrouracil (nicotinamide adenine dinucleotide, phosphate)
*DHU dehydrogenase
*hydropyrimidine dehydrogenase
*dihydropyrimidine dehydrogenase (NADP+)
Structural studies
As of late 2007, 5
structures
A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
have been solved for this class of enzymes, with
PDB accession codes , , , , and .
Function
The protein is a
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 other ...
catabolic enzyme and the initial and rate-limiting factor in the pathway of
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 by ...
and
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. I ...
catabolism
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...
. Genetic deficiency of this enzyme results in an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving
5-fluorouracil
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancrea ...
chemotherapy.
Interactive pathway map
See also
*
Dihydropyrimidine dehydrogenase deficiency
Dihydropyrimidine dehydrogenase deficiency is an autosomal recessive
metabolic disorder in which there is absent or significantly decreased activity of dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism of uracil and thymine.
In ...
, a genetic disorder
*
Cancer pharmacogenomics
Cancer pharmacogenomics is the study of how variances in the genome influences an individual’s response to different cancer drug treatments. It is a subset of the broader field of pharmacogenomics, which is the area of study aimed at understandi ...
References
Further reading
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EC 1.3.1
NADPH-dependent enzymes
Enzymes of known structure
{{1.3-enzyme-stub