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词条 Molybdopterin synthase
释义

  1. Enzyme Structure

  2. Enzyme Mechanism

  3. Biological Function

  4. Disease Relevance

  5. References

{{Infobox enzyme
| Name = Molybdopterin synthase
| EC_number = 2.8.1.12
| CAS_number =
| IUBMB_EC_number = 2/8/1/12
| GO_code =
| image =
| width =
| caption =
}}Molybdopterin synthase ({{EC number|2.8.1.12}}, MPT synthase) is an enzyme required to synthesize molybdenum cofactor (MoCo) from precursor Z (now known as cyclic pyranopterin monophosphate).[1][2] This enzyme catalyses the following chemical reaction

precursor Z + 2 [molybdopterin-synthase sulfur-carrier protein]-Gly-NH-CH2-C(O)SH + H2O molybdopterin + 2 molybdopterin-synthase sulfur-carrier protein

Molybdopterin synthase is heterodimeric and coded for by the MOCS2 gene.[3] Genetic deficiencies of enzymes, such as MPT synthase, involved in MoCo biosynthesis lead to MoCo deficiency, a rare disease that results in severe neurological abnormalities.[4][5][6][7]

Enzyme Structure

The high resolution crystal structure of MPT Synthase shows the enzyme has a heterotetrametric structure composed of two small subunits (MoaD in prokaryotes) and two large subunits (MoaE in prokaryotes) with the small subunits at opposite ends of a central large subunit dimer [1][4][5]. The C-terminus of each small subunit is inserted into a large subunit to form the active site [4]. In the enzyme’s activated form the C-terminus is present as a thiocarboxylate, which acts as the sulfur donor to precursor Z in MoCo biosynthesis [4]. 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 crystal structure of the enzyme also reveals the presence of a binding pocket for the terminal phosphate of molybdopterin and suggests a possible binding site for the pterin moiety present both in precursor Z and molybdopterin [8].

The structural similarity between ubiquitin and the small subunit of MPT Synthase hints at the evolutionary relationship of the MoCo biosynthesis pathway and the ubiquitin dependent protein degradation pathway [4][9]. Specifically, the small subunit MoaD in prokaryotes is a sequence homolog of Urm1, indicating that MPT synthase probably shares a common ancestor with ubiquitin [9].    

Enzyme Mechanism

The biosynthesis of MoCo is an old and evolutionary conserved pathway present in eukaryotes, eubacteria, and archea, which can be divided into three major steps [4]. The first step involves the conversion of a guanosine nucleotide into precursor Z [4][10]. In the following step, MPT synthase catalyzes the incorporation of the dithiolene moiety  to precursor Z, which converts it to molybdopterin (MPT) [4]. More specifically, this interconversion involves the opening of the cyclic phosphate ring of precursor Z, and the addition of two side chain sulfhydryl groups [10]. E-coli MPT synthase is activated by the formation of a thiocarboxylate group at the second glycine of its C-terminal Gly-Gly motif, which serves as the sulfur donor for the formation of the diothiolene group in MPT [5][11]. 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 [8] In the final step of MoCo biosynthesis, molybendum is incorporated to MPT by the two-domain protein gephyrin.[5][6] MPT synthase sulfurylase recharges MPT synthase with a sulfur atom after each catalytic cycle [9].

Biological Function

MPT synthase is involved in the biosynthesis of MoCo, which is essential for the activity of enzymes like xanthine dehydrogenase, aldehyde oxidase, and sulfite oxidase in humans [5]. MoCo containing enzymes typically catalyze the net transfer of an oxygen atom to and from  their substrates in a two electron redox reaction.[4]

Disease Relevance

MoCo deficiency in humans results in the combined deficiency of the MoCo-containing enzymes: sulfite oxidase, xanthine oxidase, and aldehyde oxidase [4][5][7]. Symptoms of MoCo deficiency are linked to the accumulation of toxic metabolites caused by the reduced activity of these molybdoenzymes, especially sulfite oxidase [4]. Genetic defects in MoCo biosynthesis lead to MoCo deficiency [4]. 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) [7][12]. MOCS1 is defective for group A (the majority of patients), and encodes two enzymes involved in the formation of precursor Z [7][12]. MOCS2 is defective for group B and encodes the small and large subunits of MPT synthase [7][12]. Groups A and B of deficiency show an identical phenotype, characterized by neonatal seizures, attenuated brain growth, dislocated ocular lenses, feeding difficulties, among other neurological symptoms [4][5][6][7][12].This rare but severe deficiency is an autosomal recessive trait, which usually results in early childhood death as there is currently no available treatment [4][5][6][7].

References

1. ^1 {{cite journal | vauthors = Daniels JN, Wuebbens MM, Rajagopalan KV, Schindelin H | title = Crystal structure of a molybdopterin synthase-precursor Z complex: insight into its sulfur transfer mechanism and its role in molybdenum cofactor deficiency | journal = Biochemistry | volume = 47 | issue = 2 | pages = 615–26 | date = January 2008 | pmid = 18092812 | doi = 10.1021/bi701734g }}
2. ^{{cite journal | vauthors = Wuebbens MM, Rajagopalan KV | title = Mechanistic and mutational studies of Escherichia coli molybdopterin synthase clarify the final step of molybdopterin biosynthesis | journal = The Journal of Biological Chemistry | volume = 278 | issue = 16 | pages = 14523–32 | date = April 2003 | pmid = 12571226 | doi = 10.1074/jbc.m300453200 }}
3. ^{{cite journal | vauthors = Sloan J, Kinghorn JR, Unkles SE | title = The two subunits of human molybdopterin synthase: evidence for a bicistronic messenger RNA with overlapping reading frames | journal = Nucleic Acids Research | volume = 27 | issue = 3 | pages = 854–8 | date = February 1999 | pmid = 9889283 | pmc = 148257 | doi = 10.1093/nar/27.3.854 }}
4. ^1 2 3 4 5 6 7 8 9 10 11 12 13 {{Cite journal|last=Rudolph, Michael J. and Wuebbens, Margot M. and Rajagopalan, K. V. and Schindelin, Hermann|date=2001|title=Crystal structure of molybdopterin synthase and its evolutionary relationship to ubiquitin activation|journal=Nature Structural Biology|volume=8|issue=1|pages=42–46|doi=10.1038/83034|pmid=11135669}}
5. ^1 2 3 4 5 6 7 {{Cite journal|last=Silke Leimkühler, Andrea Freuer, Jose ́ Angel Santamaria Araujo, K. V. Rajagopalan, and Ralf R. Mendel|date=2003|title=Mechanistic Studies of Human Molybdopterin Synthase Reaction and Characterization of Mutants Identified in Group B Patients of Molybdenum Cofactor Deficiency|journal=Journal of Biological Chemistry|volume=278|issue=28|pages=26127–26134|doi=10.1074/jbc.M303092200|pmid=12732628}}
6. ^1 2 3 {{Cite journal|last=Stallmeyer, B., Schwarz, G., Schulze, J., Nerlich, A., Reiss, J., Kirsch, J., Mendel, R. R.|date=1999|title=The neurotransmitter receptor-anchoring protein gephyrin reconstitutes molybdenum cofactor biosynthesis in bacteria, plants, and mammalian cells|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=96|issue=4|pages=1333–1338|pmc=15463|pmid=9990024|doi=10.1073/pnas.96.4.1333}}
7. ^1 2 3 4 5 6 {{Cite journal|last=Reiss J|date=2000|title=Genetics of molybdenum cofactor deficiency|journal=Human Genetics|volume=106|issue=2|pages=157–163|pmid=10746556|doi=10.1007/s004390051023}}
8. ^1 {{Cite journal|last=Michael J. Rudolph, Margot M. Wuebbens, Oliver Turque, K. V. Rajagopalan, Hermann Schindelin|date=2003|title=Structural Studies of Molybdopterin Synthase Provide Insights into Its Catalytic Mechanism|journal=Journal of Biological Chemistry|volume=278|issue=16|pages=14514–14522|doi=10.1074/jbc.M300449200|pmid=12571227}}
9. ^1 2 {{Cite journal|last=Wang, Chunyu and Xi, Jun and Begley, Tadhg P. and Nicholson, Linda K.|date=2001|title=Solution structure of ThiS and implications for the evolutionary roots of ubiquitin|url=https://www.nature.com/articles/nsb0101_47|journal=Nature Structural and Molecular Biology|volume=8|pages=47–51}}
10. ^1 {{Cite journal|last=Margot M. Wuebbens, K. V. Rajagopalan|date=1995|title=Investigation of the Early Steps of Molybdopterin Biosynthesis in Escherichia coli through the Use of in Vivo Labeling Studies|journal=Journal of Biological Chemistry|volume=270|issue=3|pages=1082–1087|doi=10.1074/jbc.270.3.1082}}
11. ^{{Cite journal|last=Gerrit Gutzke, Berthold Fischer, Ralf R. Mendel, Günter Schwarz|date=2001|title=Thiocarboxylation of Molybdopterin Synthase Provides Evidence for the Mechanism of Dithiolene Formation in Metal-binding Pterins|journal=Journal of Biological Chemistry|volume=276|issue=39|pages=36268–36274|doi=10.1074/jbc.M105321200|pmid=11459846}}
12. ^1 2 3 {{Cite journal|last=J. Reiss, C. Dorche, B. Stallmeyer, R. R. Mendel, N. Cohen, M. T. Zabot|date=1999|title=Human Molybdopterin Synthase Gene: Genomic Structure and Mutations in Molybdenum Cofactor Deficiency Type B|journal=Human Genetics|volume=64|issue=3|pages=706–711|pmc=1377787|pmid=10053004|doi=10.1086/302296}}
{{Sulfur-containing group transferases}}{{biochem-stub}}

1 : EC 2.8.1
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