In enzymology, a prostaglandin-F synthase (PGFS; ) 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 ...

that catalyzes 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''Z'',13''E'')-(15''S'')-9alpha,11alpha,15-trihydroxyprosta-5,13-dienoate + NADP⁺

\rightleftharpoons

(5''Z'',13''E'')-(15''S'')-9alpha,15-dihydroxy-11-oxoprosta-5,13-dienoate + NADPH + H⁺ Thus, the two

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 ...

of this enzyme are 9α,11β–PGF₂ and NADP⁺, whereas its three substrates are Prostaglandin D2, NADPH, and H⁺. PGFS is a monomeric wild-type protein that was first purified from bovine lung (PDB ID: 2F38). This enzyme belongs to the family of

aldo-keto reductase The aldo-keto reductase family is a family of proteins that are subdivided into 16 categories; these include a number of related monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase, aldose reductase, prostaglandin F synthase, xy ...

(AKR) based on its high substrate specificity, its high molecular weight (38055.48 Da) and amino acid sequence. In addition, it is categorized as C3 (AKR1C3) because it is an isoform of 3α-hydroxysteroid dehydrogenase. The function of PGFS is to catalyze the reduction of

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

s and ketones to their corresponding alcohols. In humans, these reactions take place mostly in the lungs and in the liver. More specifically, PGFS catalyzes the reduction of PGD₂ to 9α,11β–PGF₂ and PGH₂ to PGF2α by using NADPH as cofactor.

Nomenclature

This enzyme belongs to the family of

oxidoreductase In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually u ...

s, specifically those acting on the CH-OH group of donor with NAD⁺ or NADP⁺ as acceptor. 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 (5Z,13E)-(15S)-9alpha,11alpha,15-trihydroxyprosta-5,13-dienoate:NADP⁺ 11-oxidoreductase. Other names in common use include prostaglandin-D₂ 11-reductase, reductase, 15-hydroxy-11-oxoprostaglandin, PGD₂ 11-ketoreductase, PGF_2α synthetase, prostaglandin 11-ketoreductase, prostaglandin D₂-ketoreductase, prostaglandin F synthase, prostaglandin F synthetase, synthetase, prostaglandin F_2α, prostaglandin-D₂ 11-reductase, PGF synthetase, NADPH-dependent prostaglandin D₂ 11-keto reductase, and prostaglandin 11-keto reductase. This enzyme participates in

arachidonic acid metabolism Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arach ...

Structure

, 7

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 . The primary structure of prostaglandin F synthase consists of 323 amino acid residues. The secondary structure consists of 17 α-helices which contain 130 residues and 18 β-strands which contain 55 residues as well as many random coils. The tertiary structure is a single subunit. The active site of the enzyme is referred to as an (α/β)₈ barrel because it consists of 8 α-helices and 8 β-strands. More specifically, the eight α-helices surround the eight β-strands which form the cylindrical core of the active site. In addition, the active site of the enzyme contains also three random coils which help to connect the helices and strands together. The size of the active site of the enzyme is large enough not only to bind NADPH cofactor but also to bind the substrates PGD₂ or PGH₂.

Reaction

In order for the PGFS enzyme to catalyze the reduction of the substrates PGH₂ or PGD₂, the cofactor NADPH must be present in the active site. This cofactor is present deep within the cavity of the enzyme and forms a hydrogen bond with it, whereas the substrate is located closer to the mouth of the cavity which limits its interaction with PGFS. The

rate determining step In chemical kinetics, the overall rate of a reaction is often approximately determined by the slowest step, known as the rate-determining step (RDS or RD-step or r/d step) or rate-limiting step. For a given reaction mechanism, the prediction of the ...

of the catalysis is the binding of NADPH cofactor in the active site of the enzyme. This is because the binding of NADPH occurs before the binding of the substrate. NADPH is an important cofactor because it is involved in the hydride transfer which is necessary for the reduction to take place. More specifically, in order for the hydride transfer to occur, the substrate ( PGD₂) has to bind to the active site of the enzyme PGFS. The substrate binds to the active site through hydrogen bonding between the carbonyl group of PGD₂ and the hydroxyl group of

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...

(Y55) as well as one of the imidazole nitrogen of

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the d ...

(H117). The hydride shift from NADPH reduces the carbonyl group of PGD₂ and forms a new sp³ hydroxyl group ( 9α,11β–PGF₂). The protonation of the carbonyl oxygen is facilitated at low pH when

is used and at high pH when

is used for hydrogen bonding with the substrate. On the one hand,

is an ideal proton donor at low pH because of its pKa value (6.00), which means that it is protonated at a pH below 6.00. On the other hand,

is an ideal proton donor at higher pH because of its pKa value (10.1). The type of amino acid that is used for protonation depends on the substrate. For example, reduction of PGD₂ in the human body occurs at a pH range of 6-9, which makes

an ideal proton donor. The hydride that is transferred to the carbonyl oxygen of PGD₂ causes weakening of the hydrogen bond between the substrate and the enzyme. This has as a result the cleavage of the product ( 9α,11β–PGF2) from the active site of the enzyme.

Use

In general,

prostaglandins The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are deriv ...

are molecules that are used for inflammation, muscle contraction and blood clotting. Prostaglandin F synthase (PGFS) is very important enzyme because it catalyzes the formation of 9α,11β–PGF₂ and PGF2α which are critical for the contraction of bronchial, vascular and arterial smooth muscle. Also, this enzyme can be used in cancer research. Recent studies have shown that there is a correlation between high levels of PGFS in gastrointestinal tumors and the effectiveness of non-steroidal anti-inflammatory drugs (

NSAID Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...

). The inhibition of PGFS by NSAID could turn out to be a very important medicinal field in the development of anti-cancer medication.

Inhibition

Prostaglandin F synthase can be inhibited not only by

s such as

indometacin Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of pros ...

and suprofen but also by a molecule known as

bimatoprost Bimatoprost, sold under the brand name Lumigan among others, is a medication used to treat high pressure inside the eye including glaucoma. Specifically it is used for open angle glaucoma when other agents are not sufficient. It may also be used ...

(BMP). BMP, an analogue of PGD₂ is an ocular hypotensive agent that binds to the active site of the PGFS enzyme. This means that it inhibits the action of PGFS to catalyze the conversion of PGD₂ to 9α,11β–PGF₂ and PGH₂ to PGF2α because it inhibits the substrate to bind to the active site of the enzyme.

Nomenclature

Structure

Reaction

Use

Inhibition

References

Further reading