Pantothenate kinase (, PanK; CoaA) is the first

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

Coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...

(CoA) biosynthetic pathway. It phosphorylates

pantothenate 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, ...

(vitamin B₅) to form 4'-phosphopantothenate at the expense of a molecule of

adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...

( ATP). It is the rate-limiting step in the biosynthesis of CoA. Mechanism os pantothenate kinase

CoA is a necessary cofactor in all living organisms. It acts as the major

acyl group In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an alkyl group (). In organic chemistry, the acyl group (IUPAC ...

carrier in many important cellular processes, such as the

citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins ...

(

tricarboxylic acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...

) and

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

. Consequently, pantothenate kinase is a key regulatory enzyme in the CoA biosynthetic pathway.

Types

Three distinct types of PanK has been identified - PanK-I (found in bacteria), PanK-II (mainly found in eukaryotes, but also in the ''

Staphylococci ''Staphylococcus'' is a genus of Gram-positive bacteria in the family Staphylococcaceae from the order Bacillales. Under the microscope, they appear spherical (cocci), and form in grape-like clusters. ''Staphylococcus'' species are facultative ...

'') and PanK-III, also known as CoaX (found in bacteria). Eukaryotic PanK-II enzymes often occur as different isoforms, such as PanK1, PanK2, PanK3 and PanK4. In humans, multiple PanK isoforms are expressed by four genes. PANK1 gene encodes the PanK1α and PanK1β forms, and PANK2 and PANK3 encode PanK2 and PanK3, respectively.

Structure

PanK-II

PanK-II contains two

protein domain In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...

s, as illustrated in Figure 1. The A domain and A' domain each has a glycine-rich loop (sequence GXXXXGKS;

P loop P, or p, is the sixteenth letter (alphabet), letter of the Latin alphabet, used in the English alphabet, modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is English alphabet#L ...

) that is characteristic of

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 ...

-binding sites; this is where ATP is assumed to bind. located between residues 95 and 102 on the A domain The two ATP binding sites display cooperative behavior. The dimerization interface consists of two long helices, one from each monomer, that interact with each other. The

C-terminal 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 ...

ends of the helices are held together by van der Waals interactions between

valine Valine (symbol Val or V) is an α-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), an α- carboxylic acid group (which is in the deprotonat ...

and

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 ro ...

residues of each monomer. The middle of the helices is attached by hydrogen bonds between

asparagine Asparagine (symbol Asn or N) is an α-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), an α-carboxylic acid group (which is in the depro ...

residues. At the

N-terminal 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 ...

end, each helix widens and forms a four-helix bundle with two shorter helices. This bundle consists of a hydrophobic core formed by non-polar residues that utilize van der Waals forces to further stabilize the dimer. In the active site, pantothenate is oriented by hydrogen bonds between pantothenate and the side chains of aspartate, tyrosine, histidine, tyrosine, and asparagine residues. Asparagine, histidine, and arginine residues are involved in catalysis. Human PanK-II isoforms PanK1α, PanK1β, PanK2, and PanK3 have a common, highly homologous catalytic core of approximately 355 residues. PanK1α and PanK1β are both encoded by the ''PANK1'' gene and have the same catalytic domain of 363 amino acids, encoded by

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

s 2 through 7. The PanK1α transcript starts with exon 1α that encodes a 184-residue regulatory domain at 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 ...

. This region allows for feedback inhibition by free CoA and

acyl-CoA Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way ...

and regulation by

acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...

and

malonyl-CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...

. On the other hand, the PanK1β transcript starts with exon 1β, which produces a 10-residue N-terminus that does not include a feedback regulatory domain.

PanK-III

PanK-III also contains two

s, and the key catalytic residues of PanK-II are conserved. The monomer units of PanK-II and PanK-III are virtually identical, but they have distinctly different dimer assemblies. A study between the structures of ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive ...

'' type II and the ''

Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerugi ...

'' type III demonstrate that the PanK-II monomer has a loop region that is absent from the PanK-III monomer, and the PanK-III monomer has a loop region that is absent from the PanK-II monomer. This minor variation has a crucial difference on the dimerization interface in which the helices of the PanK-II dimer coil around one another and the helices of the PanK-III dimer interact at a 70° angle (Figure 2). As a result of this difference in dimerization interface between PanK-II and PanK-III, the conformations of the substrate binding sites for ATP and

are also distinct.

Catalytic Mechanism

PanK-II

A proposed mechanism of the phosphoryl transfer reaction of PanK-II is a concerted mechanism with a dissociative

transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked wi ...

. First, the ATP binds at the binding groove created by residues of the

and nearby residues. Here, the conserved

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

( Lys-101) is the key residue required for ATP binding. Additionally, the side chains of residues Lys-101, Ser-102, Glu-199, and Arg-243 orient the

in the binding groove. The

is bound and oriented by forming hydrogen bond interactions with residues Asp-127, Tyr-240, Asn-282, Tyr-175, and His-177. When both ATP and

are bound, Asp-127 deprotonates the C1

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

group of

. The oxygen from the

then attacks the γ-phosphate of the bound ATP. Here, charge stabilization of β- and γ-phosphate groups is achieved by Arg-243, Lys-101, and a coordinated Mg²⁺ ion. In this concerted mechanism, the planar

phosphorane A phosphorane (IUPAC name: λ5-phosphane) is a functional group in organophosphorus chemistry with pentavalent phosphorus. It has the general formula PR5. The parent hydride compound is the hypothetical molecule PH5. The derivative pentaphenylph ...

of the γ-phosphate is transferred in-line to the attacking oxygen of

. Finally, 4'-phosphopantothenate dissociates from PanK, followed by ADP.

Regulation of pantothenate kinase

PanK-II

The regulation of pantothenate kinase is essential to controlling the intracellular CoA concentration. Pantothenate kinase is regulated via feedback inhibition by CoA and its thioesters (i.e.,

). CoA inhibits PanK activity by competitively binding to the ATP binding site and preventing ATP binding to Lys-101. Although CoA binds at the same site as ATP, they bind in distinct orientations, and their

adenine Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its derivati ...

moieties interact with the

with nonoverlapping sets of residues. His-177, Phe-247, and Arg-106 are necessary for CoA recognition but not for ATP, and while Asn-43 and His-307 interact with the

base of ATP, His-177 and Phe-247 interact with the

base of CoA. Both molecules use Lys-101 to neutralize the charge on their respective phosphodiesters. Nonesterified CoA has more potent inhibition than its thioesters. This phenomenon is best explained by the tight fit of the

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...

group with the surrounding aromatic residues, Phe-244, Phe-259, Tyr-262, and Phe-252. Free CoA has an optimal fit, but when an

is attached to CoA, the steric hindrance makes it difficult for the thioester to interact with Phe-252. Thus, the inhibition by thioesters is less effective than that by nonesterified CoA.

PanK-III

The regulation outlined above corresponds to PanK-II. PanK-III is resistant to feedback inhibition.

Genes

In humans: * '' PANK1'', '' PANK2'', , '' PANK4''. The PANK2 gene encodes for PanK2, which regulates the formation of CoA in

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

, the cell’s energy-producing centers. PANK2 mutation is the cause of

Pantothenate kinase-associated neurodegeneration Pantothenate kinase-associated neurodegeneration (PKAN), formerly called Hallervorden–Spatz syndrome, is a genetic degenerative disease of the brain that can lead to parkinsonism, dystonia, dementia, and ultimately death. Neurodegeneration in P ...

, formerly called Hallervorden-Spatz syndrome. This rare disease presents with profound dystonia, spasticity and is often fatal.

References

External links

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