Pyruvate, Phosphate Dikinase
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Pyruvate, phosphate dikinase, or PPDK () 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 ...
in the family of
transferase A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of di ...
s 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 ...
:ATP + pyruvate + phosphate \rightleftharpoons AMP + phosphoenolpyruvate + diphosphate This enzyme has been studied primarily in plants, but it has been studied in some bacteria as well. It is a key enzyme in gluconeogenesis and photosynthesis that is responsible for reversing the reaction performed by pyruvate kinase in Embden-Meyerhof-Parnas glycolysis. It should not be confused with pyruvate, water dikinase. It belongs to the family of
transferase A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of di ...
s, to be specific, those transferring phosphorus-containing groups (
phosphotransferase Phosphotransferases are a category of enzymes ( EC number 2.7) that catalyze phosphorylation reactions. The general form of the reactions they catalyze is: :A-P + B \rightleftharpoons B-P + A Where ''P'' is a phosphate group and A and B are the do ...
s) with paired acceptors (
dikinase Dikinases are a category of enzymes that catalyze the chemical reaction :ATP + X + Y \rightleftharpoons AMP + X-''P'' + Y-''P''. Dikinases are all phosphotransferases. Their designated EC number is 2.7.9. It is one of the smallest groups of pho ...
s). This enzyme participates in
pyruvate metabolism Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compoun ...
and
carbon fixation Biological carbon fixation or сarbon assimilation is the process by which inorganic carbon (particularly in the form of carbon dioxide) is converted to organic compounds by living organisms. The compounds are then used to store energy and as ...
.


Nomenclature

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 ATP:pyruvate, phosphate phosphotransferase. Other names in common use include pyruvate, orthophosphate dikinase, pyruvate-phosphate dikinase (phosphorylating), pyruvate phosphate dikinase, pyruvate-inorganic phosphate dikinase, pyruvate-phosphate dikinase, pyruvate-phosphate ligase, pyruvic-phosphate dikinase, pyruvic-phosphate ligase, pyruvate, Pi dikinase, and PPDK.


Reaction mechanism

PPDK catalyses the conversion of
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic aci ...
to
phosphoenolpyruvate Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the ester derived from the enol of pyruvate and phosphate. It exists as an anion. PEP is an important intermediate in biochemistry. It has the highest-energy phosphate bond found (−61.9 kJ/ ...
(PEP), consuming 1 molecule of ATP, and producing one molecule of
AMP #REDIRECT Amp #REDIRECT Amp {{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
{{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
in the process. The
mechanism Mechanism may refer to: *Mechanism (engineering), rigid bodies connected by joints in order to accomplish a desired force and/or motion transmission *Mechanism (biology), explaining how a feature is created *Mechanism (philosophy), a theory that a ...
consists of 3 reversible reactions: #The enzyme PPDK binds to ATP, to produce AMP and a diphosphorylated PPDK. #The diphosphorylated PPDK binds to
inorganic phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosphor ...
, producing
diphosphate In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among othe ...
and (mono)phosphorylated PPDK. #Phosphorylated PPDK binds to pyruvate, producing phosphoenolpyruvate, and regenerating PPDK. The reaction is similar to the reaction catalysed by
pyruvate kinase Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyru ...
, which also converts pyruvate to PEP. However, pyruvate kinase catalyses an
irreversible reaction A reversible reaction is a reaction in which the conversion of reactants to products and the conversion of products to reactants occur simultaneously. : \mathit aA + \mathit bB \mathit cC + \mathit dD A and B can react to form C and D or, in the ...
, and does not consume ATP. By contrast, PPDK catalyses a reversible reaction, and consumes 1 molecule of ATP for each molecule of pyruvate converted. Currently, the details of each mechanistic step is unknown


Structure

In its active form, PPDK is a
homotetramer A tetrameric protein is a protein with a protein quaternary structure, quaternary structure of four subunits (tetrameric). Homotetramers have four identical Protein subunit, subunits (such as glutathione S-transferase), and heterotetramers are M ...
with subunits about 95
kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at ...
There are two different reaction centres about 45
Angstrom The angstromEntry "angstrom" in the Oxford online dictionary. Retrieved on 2019-03-02 from https://en.oxforddictionaries.com/definition/angstrom.Entry "angstrom" in the Merriam-Webster online dictionary. Retrieved on 2019-03-02 from https://www.m ...
s apart, in which different substrates bind. The
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 biomolecules wi ...
(ATP)
binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may inclu ...
is on the
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
, has 240
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
, and a characteristic ATP-grasp. The pyruvate/PEP binding site is on the
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
, has 340 amino acids, and an α/β-barrel fold. There is also a central domain, which contains
His His or HIS may refer to: Computing * Hightech Information System, a Hong Kong graphics card company * Honeywell Information Systems * Hybrid intelligent system * Microsoft Host Integration Server Education * Hangzhou International School, in ...
455, the primary
residue Residue may refer to: Chemistry and biology * An amino acid, within a peptide chain * Crop residue, materials left after agricultural processes * Pesticide residue, refers to the pesticides that may remain on or in food after they are applied ...
responsible for catalysis. His455 is the phosphoryl acceptor or donor residue. The structure of the enzyme suggests that the His455 arm undergoes a
swivel A swivel is a connection that allows the connected object, such as a gun, chair, swivel caster, or an anchor rode to rotate horizontally or vertically. Swivel designs A common design for a swivel is a cylindrical rod that can turn freely wi ...
ling motion to shuttle a phosphoryl group between the two reaction centres. During this swivelling, the central domain rotates at least 92 degrees, and translates 0.5 Angstroms. Studies of
crystal structures A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macrosc ...
of PPDK show that the central domain is located in different proximity to the two other domains depending on the source of the enzyme. In
maize Maize ( ; ''Zea mays'' subsp. ''mays'', from es, maíz after tnq, mahiz), also known as corn (North American and Australian English), is a cereal grain first domesticated by indigenous peoples in southern Mexico about 10,000 years ago. Th ...
, it is closer to the C-terminal, while in '' Clostridium symbiosum'', it is closer to the N-terminal. Research has shown that the PPDK binding mechanisms are similar to that of D-Ala-D-Ala ligase and
pyruvate kinase Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyru ...
. In particular, PPDK is very similar to pyruvate kinase, which also catalyses the conversion of pyruvate to phosphoenolpyruvate; however, it does so without a phosphorylated-enzyme intermediate. Though their amino acid sequences are different, residues key to catalysis are preserved in both enzymes. Point-mutagenesis experiments have shown that catalytic residues include
Arg Arg or ARG may refer to: Places *''Arg'' () means "citadel" in Persian, and may refer to: **Arg, Iran, a village in Fars Province, Iran **Arg (Kabul), presidential palace in Kabul, Afghanistan **Arg, South Khorasan, a village in South Khorasan P ...
561,
Arg Arg or ARG may refer to: Places *''Arg'' () means "citadel" in Persian, and may refer to: **Arg, Iran, a village in Fars Province, Iran **Arg (Kabul), presidential palace in Kabul, Afghanistan **Arg, South Khorasan, a village in South Khorasan P ...
617, Glu745, Asn768, and Cys831 (numbering relative to the ''C, symbiosum'' protein, ).


Biological function and evolution

PPDK is used in the
C4 pathway carbon fixation or the Hatch–Slack pathway is one of three known photosynthetic processes of carbon fixation in plants. It owes the names to the 1960's discovery by Marshall Davidson Hatch and Charles Roger Slack that some plants, when su ...
, to improve the efficiency of
carbon dioxide Carbon dioxide (chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is transpar ...
fixation. In environments where there is a lot of light, the rate of
photosynthesis Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored i ...
in plants is limited by the rate of carbon dioxide (CO2) uptake. This can be improved by using a series of chemical reactions to transport CO2 from
mesophyll A leaf ( : leaves) is any of the principal appendages of a vascular plant stem, usually borne laterally aboveground and specialized for photosynthesis. Leaves are collectively called foliage, as in "autumn foliage", while the leaves, ste ...
cells (which are located on the outside of a leaf) to
bundle sheath A vascular bundle is a part of the transport system in vascular plants. The transport itself happens in the stem, which exists in two forms: xylem and phloem. Both these tissues are present in a vascular bundle, which in addition will inclu ...
cells (which are located inside the cells). PPDK converts pyruvate to PEP, which reacts with CO2 to produce
oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
. When CO2 is released in the bundle sheath cells, pyruvate is regenerated, and the cycle continues. Though the reaction catalysed by PPDK is reversible, PEP is favoured as the product in biological conditions. This is due to the
basic BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Thomas E. Kurtz at Dartmouth College ...
pH in the stroma, where the reaction occurs, as well as high concentrations of
adenylate kinase Adenylate kinase ( ECbr>2.7.4.3 (also known as ADK or myokinase) is a phosphotransferase enzyme that catalyzes the interconversion of the various adenosine phosphates (ATP, ADP, and AMP). By constantly monitoring phosphate nucleotide levels insid ...
and
pyrophosphatase Pyrophosphatases, also known as diphosphatases, are acid anhydride hydrolases that act upon diphosphate bonds. Examples include: * Inorganic pyrophosphatase, which acts upon the free pyrophosphate ion * Tobacco acid pyrophosphatase, which cata ...
. Because these two enzymes catalyse
exergonic An exergonic process is one which there is a positive flow of energy from the system to the surroundings. This is in contrast with an endergonic process. Constant pressure, constant temperature reactions are exergonic if and only if the Gibbs fr ...
reactions involving AMP, and disphosphate, respectively, they drive the PPDK-catalysed reaction forward. Because PPDK consumes ATP, the C4 pathway is unfavourable for plants in environments with little access to light, as they are unable to produce large quantities of ATP. PPDK is highly abundant in C4 leaves, comprising up to 10% of total
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
. Research has shown that the enzyme is about 96% identical in different
species In biology, a species is the basic unit of classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of the appropriate s ...
of plants.
Hybrid Hybrid may refer to: Science * Hybrid (biology), an offspring resulting from cross-breeding ** Hybrid grape, grape varieties produced by cross-breeding two ''Vitis'' species ** Hybridity, the property of a hybrid plant which is a union of two dif ...
ization experiments revealed that the genetic differences correlate with the extent to which the plants perform the C4 pathway – the uncommon sequences exist in plants which also display C3 characteristics. PPDK is also found in small quantities in C3 plants. Evolutionary history suggests that it once had a role in
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
like the similar
pyruvate kinase Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyru ...
, and eventually
evolved Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation t ...
into the C4 pathway. Besides plants, PPDK is also found in the parasitic ameoba ''
Entamoeba histolytica ''Entamoeba histolytica'' is an anaerobic parasitic amoebozoan, part of the genus ''Entamoeba''. Predominantly infecting humans and other primates causing amoebiasis, ''E. histolytica'' is estimated to infect about 35-50 million people worldwid ...
'' () and the bacteria ''Clostridium symbiosum'' (; as well as other bacteria). In those two organisms PPDK functions similarly to (and sometimes in place of) pyruvate kinase, catalyzing the reaction in the ATP-producing direction as a part of glycolysis. Inhibitors for the ''Entamoeba'' PPDK have been proposed as
amebicide An amebicide (or amoebicide) is an agent that is destructive to amoeba, especially parasitic amoeba that cause amoebiasis. Entamoeba * Metronidazole, or a related drug such as Tinidazole, Secnidazole or Ornidazole, is used to destroy amoebae that h ...
s against this organism.


Regulation

Plant PPDK is regulated by the pyruvate, phosphate dikinase regulatory protein (PDRP). When levels of light are high, PDRP dephosphorylates Thr456 on PPDK using
AMP #REDIRECT Amp #REDIRECT Amp {{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
{{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
, thus activating the enzyme. PDRP deactivates PPDK by phosphorylating the same
threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
residue Residue may refer to: Chemistry and biology * An amino acid, within a peptide chain * Crop residue, materials left after agricultural processes * Pesticide residue, refers to the pesticides that may remain on or in food after they are applied ...
, using
diphosphate In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among othe ...
. PDRP is a unique regulator because it catalyses both activation and deactivation of PPDK, through two different mechanisms. Research on
maize Maize ( ; ''Zea mays'' subsp. ''mays'', from es, maíz after tnq, mahiz), also known as corn (North American and Australian English), is a cereal grain first domesticated by indigenous peoples in southern Mexico about 10,000 years ago. Th ...
PPDK suggests that
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
s, terminator sequences, and perhaps other enhancer sequences, act cooperatively to increase the level of functional and stable
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
. PPDK
cDNA In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a speci ...
was expressed only slightly in transgenic
rice Rice is the seed of the grass species ''Oryza sativa'' (Asian rice) or less commonly ''Oryza glaberrima ''Oryza glaberrima'', commonly known as African rice, is one of the two domesticated rice species. It was first domesticated and grown i ...
, compared to intact DNA which saw significant expression.


Structural studies

As of early 2018, 14
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 , , , , , , , , , , , , , .


References


Further reading

* * * * {{Portal bar, Biology, border=no EC 2.7.9 Enzymes of known structure