Molybdopterin synthase (, MPT synthase) is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

required to synthesize

molybdopterin Molybdopterins are a class of cofactors found in most molybdenum-containing and all tungsten-containing enzymes. Synonyms for molybdopterin are: MPT and pyranopterin-dithiolate. The nomenclature for this biomolecule can be confusing: Molybdopte ...

(MPT) from precursor Z (now known as cyclic pyranopterin monophosphate). Molydopterin is subsequently complexed with

molybdenum Molybdenum is a chemical element; it has Symbol (chemistry), symbol Mo (from Neo-Latin ''molybdaenum'') and atomic number 42. The name derived from Ancient Greek ', meaning lead, since its ores were confused with lead ores. Molybdenum minerals hav ...

to form molybdenum cofactor (MoCo). MPT synthase catalyses the following

chemical reaction A chemical reaction is a process that leads to the chemistry, chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an Gibbs free energy, ...

: : precursor Z + 2 olybdopterin-synthase sulfur-carrier proteinGly-NH-CH₂-C(O)SH + H₂O

\rightleftharpoons

molybdopterin + 2 molybdopterin-synthase sulfur-carrier protein Molybdopterin synthase is

heterodimeric In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...

and coded for by the

MOCS2 Molybdenum cofactor synthesis protein 2A and molybdenum cofactor synthesis protein 2B are a pair of proteins that in humans are encoded from the same ''MOCS2'' gene.: MOCS2 molybdenum cofactor synthesis 2 These two proteins dimerize to form moly ...

gene. Genetic deficiencies of enzymes such as MPT synthase, which are involved in MoCo

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

, lead to MoCo deficiency, a rare disease that results in severe neurological abnormalities.

Structure

The high resolution

crystal structure In crystallography, crystal structure is a description of ordered arrangement of atoms, ions, or molecules in a crystalline material. Ordered structures occur from intrinsic nature of constituent particles to form symmetric patterns that repeat ...

of MPT synthase shows the enzyme has a heterotetrametric structure composed of two small subunits (MoaD in

prokaryotes A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Greek (), meaning 'before', and (), meaning 'nut' ...

) and two large subunits (MoaE in prokaryotes) with the small subunits at opposite ends of a central large subunit

dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer ** TH-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * ...

. The C-terminus of each small subunit is inserted into a large subunit to form the

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...

. In the enzyme's activated form the C-terminus is present as a thiocarboxylate, which acts as the

sulfur Sulfur ( American spelling and the preferred IUPAC name) or sulphur ( Commonwealth spelling) is a chemical element; it has symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms ...

donor to precursor Z in MoCo

. As a result, the active site of the enzyme must be in close proximity to the C-terminus of the small subunit (i.e. MoaD in prokaryotes). The high resolution

of the enzyme also reveals the presence of a binding pocket for the terminal

phosphate Phosphates are the naturally occurring form of the element phosphorus. 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 orthop ...

of molybdopterin and suggests a possible binding site for the

pterin Pterin is a heterocyclic compound composed of a pteridine ring system, with a " keto group" (a lactam) and an amino group on positions 4 and 2 respectively. It is structurally related to the parent bicyclic heterocycle called pteridine. Pter ...

moiety Moiety may refer to: __NOTOC__ Anthropology * Moiety (kinship), either of two groups into which a society is divided ** A division of society in the Iroquois societal structure in North America ** An Australian Aboriginal kinship group ** Native Ha ...

present both in precursor Z and molybdopterin. The structural similarity between

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

and the small subunit of MPT synthase hints at the evolutionary relationship of the MoCo

pathway and the ubiquitin dependent

protein degradation Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...

pathway. Specifically, the small subunit MoaD in prokaryotes is a sequence homolog of Urm1, indicating that ''MPT synthase'' probably shares a

common ancestor Common descent is a concept in evolutionary biology applicable when one species is the ancestor of two or more species later in time. According to modern evolutionary biology, all living beings could be descendants of a unique ancestor commonl ...

with ubiquitin.

Mechanism

The

of MoCo is an old and evolutionary conserved pathway present in

eukaryote The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

eubacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among the ...

, and

archea Archaea ( ) is a domain of organisms. Traditionally, Archaea only included its prokaryotic members, but this has since been found to be paraphyletic, as eukaryotes are known to have evolved from archaea. Even though the domain Archaea cladis ...

, which can be divided into three major steps. The first step involves the conversion of a

guanosine Guanosine (symbol G or Guo) is a purine nucleoside comprising guanine attached to a ribose ( ribofuranose) ring via a β-N9- glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate (GMP), cyclic guanosine monophosp ...

nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

into precursor Z. In the following step, MPT synthase

catalyzes Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

the incorporation of the

dithiolene Dithiolene metal complexes are complexes containing 1,2-dithiolene ligands. 1,2-Dithiolene ligands, a particular case of 1,2-dichalcogenolene species along with 1,2-diselenolene derivatives, are unsaturated bidentate ligand wherein the two dono ...

moiety to precursor Z, which converts it to molybdopterin. More specifically, this interconversion involves the opening of the cyclic phosphate ring of precursor Z, and the addition of two side chain

sulfhydryl group 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 grou ...

E-coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escherichia'' that is commonly found ...

''MPT synthase'' is activated by the formation of a thiocarboxylate group at the second

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...

of its

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy 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 t ...

Gly-Gly motif, which serves as the

donor for the formation of the diothiolene group in MPT. That is, the mechanism on ''MPT synthase'' depends on the interconversion between the activated form of MoaD with the thiocarboxylate group and the MoaE protein In the final step of MoCo

, molybendum is incorporated to MPT by the two-domain

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

gephyrin Gephyrin is a protein that in humans is encoded by the ''GPHN'' gene. This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subu ...

. MPT synthase sulfurylase recharges MPT synthase with a sulfur atom after each catalytic cycle.

Biological function

MPT synthase is involved in the

of MoCo, which is essential for the activity of enzymes like

xanthine dehydrogenase Xanthine dehydrogenase, also known as XDH, is a protein that, in humans, is encoded by the ''XDH'' gene. Function Xanthine dehydrogenase belongs to the group of molybdenum-containing hydroxylases involved in the oxidative metabolism of purin ...

aldehyde oxidase Aldehyde oxidase (AO) is a metabolizing enzyme, located in the cytosolic compartment of tissues in many organisms. AO catalyzes the oxidation of aldehydes into carboxylic acid, and in addition, catalyzes the hydroxylation of some heterocycles. ...

, and

sulfite oxidase Sulfite oxidase () is an enzyme in the mitochondria of all eukaryotes, with exception of the yeasts. It oxidizes sulfite to sulfate and, via cytochrome c, transfers the electrons produced to the electron transport chain, allowing generation of ...

in humans. MoCo containing enzymes typically catalyze the net transfer of an

oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...

atom Atoms are the basic particles of the chemical elements. An atom consists of a atomic nucleus, nucleus of protons and generally neutrons, surrounded by an electromagnetically bound swarm of electrons. The chemical elements are distinguished fr ...

to and from their substrates in a two

electron The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...

redox reaction Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

Disease relevance

MoCo deficiency in humans results in the combined deficiency of the MoCo-containing enzymes:

xanthine oxidase Xanthine oxidase (XO or XAO) is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to ...

, and

. Symptoms of MoCo deficiency are linked to the accumulation of toxic

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s caused by the reduced activity of these molybdoenzymes, especially sulfite oxidase.

Genetic defects A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are ...

in MoCo

lead to MoCo deficiency. These genetic defects affect the formation of precursor Z (known as group A MoCo deficiency) or the conversion of precursor Z to MoCo by ''MPT synthase'' (known as group B MoCo deficiency). MOCS1 is defective for group A (the majority of patients), and encodes two enzymes involved in the formation of precursor Z.

is defective for group B and encodes the small and large subunits of ''MPT synthase''. Groups A and B of deficiency show an identical

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

, characterized by neonatal seizures, attenuated brain growth, dislocated ocular lenses, feeding difficulties, among other neurological symptoms. This rare but severe deficiency is an

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...

recessive trait In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...

, which usually results in early childhood death as there is currently no available treatment.

References

{{Sulfur-containing group transferases EC 2.8.1