Molybdopterin

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Molybdopterin
MoPterin.png
Names
IUPAC name
[2-amino-4-oxo-6,7-bis(sulfanyl)-3,5,5~{a},8,9~{a},10-hexahydropyrano[3,2-g]pteridin-8-yl]methyl dihydrogen phosphate [1]
Identifiers
3D model (JSmol)
MeSH molybdopterin
PubChem CID
UNII
  • [2] :InChI=1S/C10H14N5O6PS2/c11-10-14-7-4(8(16)15-10)12-3-6(24)5(23)2(21-9(3)13-7)1-20-22(17,18)19/h2-3,9,12,23-24H,1H2,(H2,17,18,19)(H4,11,13,14,15,16)
    Key: HPEUEJRPDGMIMY-UHFFFAOYSA-N [3] [4]
  • based on the images on this page:NC(=N1)NC(=O)C2=C1N[C@H]3[C@@H](N2)C(S)=C(S)[C@H](O3)COP([O-])([O-])=O
  • from the PubChem page; several discrepancies with images on this page:C(C1C(=C(C2C(O1)NC3=C(N2)C(=O)NC(=N3)N)S)S)OP(=O)(O)O
  • with molybdenum; based on this image:NC(=N1)NC(=O)C2=C1N[C@H]3[C@@H](N2)C(S4)=C(S[Mo]4(=O)(=O)O)[C@H](O3)COP([O-])([O-])=O
Properties
C
10H
10N
5O
6PS
2 + R groups
Molar mass 394.33 g/mol (R=H)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Four steps of molybdenum cofactor (Moco) biosynthetic pathway occurring in bacteria and humans: (i) radical-mediated cyclization guanosine 5'-triphosphate (GTP) to (8S)-3,8-cyclo-7,8-dihydroguanosine-5-triphosphate (3,8-cH2GTP), (ii) formation of cyclic pyranopterin monophosphate (cPMP) from the 3,8-cH2GTP, (iii) conversion of cPMP into molybdopterin (MPT), (iv) insertion of molybdate into MPT to form Moco (human enzymes in parentheses). Moco Biosynthetic Pathway.pdf
Four steps of molybdenum cofactor (Moco) biosynthetic pathway occurring in bacteria and humans: (i) radical-mediated cyclization guanosine 5'-triphosphate (GTP) to (8S)‑3,8‐cyclo‑7,8‑dihydroguanosine-5́‑triphosphate (3,8‑cH2GTP), (ii) formation of cyclic pyranopterin monophosphate (cPMP) from the 3,8‑cH2GTP, (iii) conversion of cPMP into molybdopterin (MPT), (iv) insertion of molybdate into MPT to form Moco (human enzymes in parentheses).

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: Molybdopterin itself contains no molybdenum; rather, this is the name of the ligand (a pterin ) that will bind the active metal. After molybdopterin is eventually complexed with molybdenum, the complete ligand is usually called molybdenum cofactor.

Contents

Molybdopterin consists of a pyranopterin, a complex heterocycle featuring a pyran fused to a pterin ring. In addition, the pyran ring features two thiolates, which serve as ligands in molybdo- and tungstoenzymes. In some cases, the alkyl phosphate group is replaced by an alkyl diphosphate nucleotide. Enzymes that contain the molybdopterin cofactor include xanthine oxidase, DMSO reductase, sulfite oxidase, and nitrate reductase.

The only molybdenum-containing enzymes that do not feature molybdopterins are the nitrogenases (enzymes that fix nitrogen). These contain an iron-sulfur center of a very different type, which also contains molybdenum. [5]

Biosynthesis

Unlike many other cofactors, molybdenum cofactor (Moco) cannot be taken up as a nutrient. The cofactor thus requires de novo biosynthesis. Molybdenum cofactor biosynthesis occurs in four steps: (i) the radical-mediated cyclization of nucleotide, guanosine triphosphate (GTP), to (8S)‑3',8‐cyclo‑7,8‑dihydroguanosine 5'‑triphosphate (3',8‑cH2GTP), (ii) the formation of cyclic pyranopterin monophosphate (cPMP) from the 3',8‑cH2GTP, (iii) the conversion of cPMP into molybdopterin (MPT), (iv) the insertion of molybdate into MPT to form Moco. [6] [7]

Two enzyme-mediated reactions convert guanosine triphosphate to the cyclic phosphate of pyranopterin. One of these enzymes is a radical SAM, a family of enzymes often associated with C—X bond-forming reactions (X = S, N). [8] [7] [6] This intermediate pyranopterin is then converted to the molybdopterin via the action of three further enzymes. In this conversion, the enedithiolate is formed, although the substituents on sulfur remain unknown. Sulfur is conveyed from cysteinyl persulfide in a manner reminiscent of the biosynthesis of iron-sulfur proteins. The monophosphate is adenylated (coupled to ADP) in a step that activates the cofactor toward binding Mo or W. These metals are imported as their oxyanions, molybdate, and tungstate.

In some enzymes, such as xanthine oxidase, the metal is bound to one molybdopterin, whereas, in other enzymes, e.g., DMSO reductase, the metal is bound to two molybdopterin cofactors. [9]

Models for the active sites of enzymes molybdopterin-containing enzymes are based on a class of ligands known as dithiolenes. [10]

Tungsten derivatives

Some bacterial oxidoreductases use tungsten in a similar manner as molybdenum by using it in a tungsten-pterin complex, with molybdopterin. Thus, molybdopterin may complex with either molybdenum or tungsten. Tungsten-using enzymes typically reduce free carboxylic acids to aldehydes. [11]

The first tungsten-requiring enzyme to be discovered also requires selenium (though the precise form is unknown). In this case, the tungsten-selenium pair has been speculated to function analogously to the molybdenum-sulfur pairing of some molybdenum cofactor-requiring enzymes. [12] Although a tungsten-containing xanthine dehydrogenase from bacteria has been found to contain tungsten-molybdopterin and also non-protein-bound selenium (thus removing the possibility of selenium in selenocysteine or selenomethionine form), a tungsten-selenium molybdopterin complex has not been definitively described. [13]

Enzymes that use molybdopterin

Enzymes that use molybdopterin as cofactor or prosthetic group are given below. [5] Molybdopterin is a:

See also

Related Research Articles

<span class="mw-page-title-main">Molybdenum</span> Chemical element, symbol Mo and atomic number 42

Molybdenum is a chemical element with the symbol Mo and atomic number 42 which is located in period 5 and group 6. The name is from Neo-Latin molybdaenum, which is based on Ancient Greek Μόλυβδος molybdos, meaning lead, since its ores were confused with lead ores. Molybdenum minerals have been known throughout history, but the element was discovered in 1778 by Carl Wilhelm Scheele. The metal was first isolated in 1781 by Peter Jacob Hjelm.

<span class="mw-page-title-main">Xanthine oxidase</span> Class of enzymes

Xanthine oxidase 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 uric acid. These enzymes play an important role in the catabolism of purines in some species, including humans.

<span class="mw-page-title-main">Pterin</span> Chemical compound

Pterin is a heterocyclic compound composed of a pteridine ring system, with a "keto group" and an amino group on positions 4 and 2 respectively. It is structurally related to the parent bicyclic heterocycle called pteridine. Pterins, as a group, are compounds related to pterin with additional substituents. Pterin itself is of no biological significance.

<span class="mw-page-title-main">Metal dithiolene complex</span>

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 donor atoms are sulfur. 1,2-Dithiolene metal complexes are often referred to as "metal dithiolenes", "metallodithiolenes" or "dithiolene complexes". Most molybdenum- and tungsten-containing proteins have dithiolene-like moieties at their active sites, which feature the so-called molybdopterin cofactor bound to the Mo or W.

DMSO reductase is a molybdenum-containing enzyme that catalyzes reduction of dimethyl sulfoxide (DMSO) to dimethyl sulfide (DMS). This enzyme serves as the terminal reductase under anaerobic conditions in some bacteria, with DMSO being the terminal electron acceptor. During the course of the reaction, the oxygen atom in DMSO is transferred to molybdenum, and then reduced to water.

<span class="mw-page-title-main">Sulfite oxidase</span>

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 ATP in oxidative phosphorylation. This is the last step in the metabolism of sulfur-containing compounds and the sulfate is excreted.

<span class="mw-page-title-main">Formate dehydrogenase</span>

Formate dehydrogenases are a set of enzymes that catalyse the oxidation of formate to carbon dioxide, donating the electrons to a second substrate, such as NAD+ in formate:NAD+ oxidoreductase (EC 1.17.1.9) or to a cytochrome in formate:ferricytochrome-b1 oxidoreductase (EC 1.2.2.1). This family of enzymes has attracted attention as inspiration or guidance on methods for the carbon dioxide fixation, relevant to global warming.

In enzymology, an ethylbenzene hydroxylase (EC 1.17.99.2) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">MOCS1</span> Protein-coding gene in the species Homo sapiens

Molybdenum cofactor biosynthesis protein 1 is a protein that in humans and other animals, fungi, and cellular slime molds, is encoded by the MOCS1 gene.

Molybdenum cofactor deficiency is a rare human disease in which the absence of molybdopterin – and consequently its molybdenum complex, commonly called molybdenum cofactor – leads to accumulation of toxic levels of sulphite and neurological damage. Usually this leads to death within months of birth, due to the lack of active sulfite oxidase. Furthermore, a mutational block in molybdenum cofactor biosynthesis causes absence of enzyme activity of xanthine dehydrogenase/oxidase and aldehyde oxidase.

A molybdenum cofactor is a biochemical cofactor that contains molybdenum.

Molybdopterin synthase (EC 2.8.1.12, MPT synthase) is an enzyme required to synthesize molybdopterin (MPT) from precursor Z (now known as cyclic pyranopterin monophosphate). Molydopterin is subsequently complexed with molybdenum to form molybdenum cofactor (MoCo). MPT synthase catalyses the following chemical reaction:

The aldehyde oxidase and xanthine dehydrogenase, a/b hammerhead domain is an evolutionary conserved protein domain.

Dimethyl sulfide:cytochrome c2 reductase (EC 1.8.2.4) is an enzyme with systematic name dimethyl sulfide:cytochrome-c2 oxidoreductase. It is also known by the name dimethylsulfide dehydrogenase (Ddh). This enzyme catalyses the following chemical reaction

Molybdenum cofactor sulfurtransferase (EC 2.8.1.9, molybdenum cofactor sulfurase, ABA3, MoCo sulfurase, MoCo sulfurtransferase) is an enzyme with systematic name L-cysteine:molybdenum cofactor sulfurtransferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Aldehyde ferredoxin oxidoreductase</span>

In enzymology, an aldehyde ferredoxin oxidoreductase (EC 1.2.7.5) is an enzyme that catalyzes the chemical reaction

In enzymology, a formylmethanofuran dehydrogenase (EC 1.2.99.5) is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">Fosdenopterin</span> Medication

Fosdenopterin, sold under the brand name Nulibry, is a medication used to reduce the risk of death due to a rare genetic disease known as molybdenum cofactor deficiency type A.

<span class="mw-page-title-main">Molybdenum in biology</span> Use of Molybdenum by organisms

Molybdenum is an essential element in most organisms. It is most notably present in nitrogenase which is an essential part of nitrogen fixation.

References

  1. ↑ "HPEUEJRPDGMIMY-UHFFFAOYSA-N". pubchem.ncbi.nlm.nih.gov. Retrieved 4 February 2019. IUPAC Name [2-amino-4-oxo-6,7-bis(sulfanyl)-3,5,5~{a},8,9~{a},10-hexahydropyrano[3,2-g]pteridin-8-yl]methyl dihydrogen phosphate
  2. ↑ "HPEUEJRPDGMIMY-UHFFFAOYSA-N". pubchem.ncbi.nlm.nih.gov. Retrieved 4 February 2019. InChI InChI=1S/C10H14N5O6PS2/c11-10-14-7-4(8(16)15-10)12-3-6(24)5(23)2(21-9(3)13-7)1-20-22(17,18)19/h2-3,9,12,23-24H,1H2,(H2,17,18,19)(H4,11,13,14,15,16)
  3. ↑ "[2-Amino-4-oxo-6,7-bis(sulfanyl)-3,5,5a,8,9a,10-hexahydropyrano[3,2-g]pteridin-8-yl]methyl dihydrogen phosphate". pubchem.ncbi.nlm.nih.gov. Retrieved 4 February 2019. InChI=1S/C10H14N5O6PS2/c11-10-14-7-4(8(16)15-10)12-3-6(24)5(23)2(21-9(3)13-7)1-20-22(17,18)19/h2-3,9,12,23-24H,1H2,(H2,17,18,19)(H4,11,13,14,15,16)
  4. ↑ "HPEUEJRPDGMIMY-UHFFFAOYSA-N". pubchem.ncbi.nlm.nih.gov. Retrieved 4 February 2019. InChI Key HPEUEJRPDGMIMY-UHFFFAOYSA-N
  5. 1 2 Structure, synthesis, empirical formula for the di-sulfhydryl. Archived 2016-06-04 at the Wayback Machine Accessed Nov. 16, 2009.
  6. 1 2 Hover BM, Tonthat NK, Schumacher MA, Yokoyama K (May 2015). "Mechanism of pyranopterin ring formation in molybdenum cofactor biosynthesis". Proc Natl Acad Sci USA. 112 (20): 6347–52. Bibcode:2015PNAS..112.6347H. doi: 10.1073/pnas.1500697112 . PMC   4443348 . PMID   25941396.
  7. 1 2 Hover BM, Loksztejn A, Ribeiro AA, Yokoyama K (April 2013). "Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis". J Am Chem Soc. 135 (18): 7019–32. doi:10.1021/ja401781t. PMC   3777439 . PMID   23627491.
  8. ↑ Mendel, R. R.; Leimkuehler, S. (2015). "The biosynthesis of the molybdenum cofactors". J. Biol. Inorg. Chem. 20 (2): 337–347. doi:10.1007/s00775-014-1173-y. PMID   24980677. S2CID   2638550.
  9. ↑ Schwarz, G. & Mendel, R. R. (2006). "Molybdenum cofactor biosynthesis and molybdenum enzymes". Annual Review of Plant Biology. 57: 623–647. doi:10.1146/annurev.arplant.57.032905.105437. PMID   16669776.
  10. ↑ Kisker, C.; Schindelin, H.; Baas, D.; Rétey, J.; Meckenstock, R.U.; Kroneck, P.M.H. (1999). "A structural comparison of molybdenum cofactor-containing enzymes". FEMS Microbiol. Rev. 22 (5): 503–521. doi: 10.1111/j.1574-6976.1998.tb00384.x . PMID   9990727.
  11. ↑ Lassner, Erik (1999). Tungsten: Properties, Chemistry, Technology of the Element, Alloys and Chemical Compounds. Springer. pp. 409–411. ISBN   978-0-306-45053-2.
  12. ↑ Stiefel, E. I. (1998). "Transition metal sulfur chemistry and its relevance to molybdenum and tungsten enzymes" (PDF). Pure Appl. Chem. 70 (4): 889–896. doi:10.1351/pac199870040889. S2CID   98647064.
  13. ↑ Schräder T, Rienhöfer A, Andreesen JR (September 1999). "Selenium-containing xanthine dehydrogenase from Eubacterium barkeri". Eur. J. Biochem. 264 (3): 862–71. doi: 10.1046/j.1432-1327.1999.00678.x . PMID   10491134.
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