Mo-molybdopterin cofactor biosynthetic process (start in mito matrix)

[hattrill]

Only the first step of Mo-molybdopterin cofactor biosynthetic process is performed in the mitochondria catalysed by Mocs1. The mitochondrial exporter for precursor Z is unknown.

Dmel Model

Notes:

Summary for D.mel: Moco biosynthesis initiates in the mitochondria with the Fe-S protein Mocs1 and continues in the cytosol with Mocs2, Mocs3, and Cinnamon producing Moco. Maroon-like sulfurates Moco for incorporation into Xdh and Aox.

Moco biosynthesis starts within mitochondria with a complex rearrangement reaction in which the C8 atom of the GTP purine is inserted between the 2′ and 3′-ribose carbon atoms. This is represented by GTP 3',8'-cyclase activity followed by cyclic pyranopterin monophosphate synthase activity to produce cyclic pyranopterin monophosphate (cPMP or precursor Z). This is carried out by a Mocs1, a complex of two alternatively spliced forms (Mocs1A-Mocs1B) which together to form the active enzyme). Cyclic pyranopterin is transported to the cytosol (unknown transporter) and is acted on by molybdopterin synthase (MOCS2) (a heterotetrameric complex formed by Mocs2A and Mocs2B in Dmel) to produce molybdopterin (MPT). In this reaction, dithiolene is introduced into cPMP, thus forming MPT. The formation of MPT is not a catalytic reaction, therefore MPT synthase needs to be regenerated upon each reaction step. This is catalyzed by the enzyme MPT-synthase sulfurase, Mocs3. The cysteine desulfurase Nfs1 is a likely candidate to function as sulfur donor for the MOCS3-catalzyed resulfuration step.

Physiologically active Moco consists of both (Molybdenum) Mo and MPT, where Mo is coordinated by the dithiolene function of MPT. The metal insertion reaction is performed by GPHN (gephyrin, known as cinnamon (cin) in Dmel) in two separate steps, starting with the adenylation of MPT and then the insertion of Mo into the dithiolene group and the hydrolysis of MPT-AMP yielding active Moco (Mo-molybdopterin cofactor). After molybdenum insertion into MPT, Moco is either inserted into Suox (shop in Dmel) or further modified by exchanging an oxo ligand by a sulfido group by MOCOS (maroon-like (mal)) molybdenum cofactor sulfurase Sulfation of molybdenum is essential for xanthine dehydrogenase (XDH) and aldehyde oxidase (ADO) enzymes

Refs: Cell biology of molybdenum in plants and humans and Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Drosophila Life Cycle by Controlling Cell Metabolism

[ValWood]

Interesting.
Saccharomyces cerevisiae and more than 75% of the Saccharomycotina yeast species cannot synthesize molybdopterin cofactor.
I am presuming pombe is one of these but not sure. We don't have anything annotated. I guess we still have Molybdenum dependent enzymes and need transporters?
CC @PCarme

[hattrill]

That's very interesting. I only know of 3 Moco-containing enzymes in Dmel and they do not seem to have orthologs in yeast (sc or sp)
ry xanthine dehydrogenase http://flybase.org/reports/FBgn0003308.htm
AOX1 Aldehyde oxidase 1 http://flybase.org/reports/FBgn0267408.htm
shop sulfite oxidase http://flybase.org/reports/FBgn0030966.htm (some single hits in DIOPT, but look like not real orthologs)

[ValWood]

Is there a complete list of molybdopterin requiring enzymes anywhere?
Do bacteria have this?

[ValWood]

Do bacteria have this? (yes)

[hattrill]

"While conserved genes for Moco biosynthesis are found in bacteria, archaea, fungi, plants and animals, it has long been proposed that, with the exception of some organisms like yeast that apparently possesses no molybdoenzymes [158], the biosynthesis of Moco is conserved in all organisms." https://www.sciencedirect.com/science/article/pii/S0005272812010821

Moco-containing enzymes seem to be mainly in these classes of enzymes:
nitrogenase
xanthine oxidase
sulfite oxidase
Dimethylsulfoxide reductase
https://pmc.ncbi.nlm.nih.gov/articles/PMC2670968/

seem to be more in bacteria and archaea

[hattrill]

wikipedia list: https://en.wikipedia.org/wiki/Category:Molybdenum_enzymes

[ValWood]

of this list we appear to have only a
NADH/NADPH-dependent indole-3-acetaldehyde reductase
https://www.pombase.org/reference/PMID:16813561
but maybe this is incorrect (this is one of my 'unknowns'