ADI1, a methionine salvage pathway enzyme, is required for Drosophila fecundity

Abstract

BackgroundMethionine, an essential amino acid, is required for protein synthesis and normal cell metabolism. The transmethylation pathway and methionine salvage pathway (MTA cycle) are two major pathways regulating methionine metabolism. Recently, methionine has been reported to play a key role in Drosophila fecundity.ResultsHere, we revealed that the MTA cycle plays a crucial role in Drosophila fecundity using the mutant of aci-reductone dioxygenase 1 (DADI1), an enzyme in the MTA cycle. In dietary restriction condition, the egg production of adi1 mutant flies was reduced compared to that of control flies. This fecundity defect in mutant flies was rescued by reintroduction of Dadi1 gene. Moreover, a functional homolog of human ADI1 also recovered the reproduction defect, in which the enzymatic activity of human ADI1 is required for normal fecundity. Importantly, methionine supply rescued the fecundity defect in Dadi1 mutant flies. The detailed analysis of Dadi1 mutant ovaries revealed a dramatic change in the levels of methionine metabolism. In addition, we found that three compounds namely, methionine, SAM and Methionine sulfoxide, respectively, may be required for normal fecundity.ConclusionsIn summary, these results suggest that ADI1, an MTA cycle enzyme, affects fly fecundity through the regulation of methionine metabolism.

The Metal Drives the Chemistry: Dual Functions of Acireductone Dioxygenase

“…7 In dietary restriction conditions, the egg production of acireductone dioxygenase 1 (Δ ADI1 ) mutant flies was reduced compared to that of control flies. This fecundity defect in mutant flies was rescued by either methionine supply or reintroduction of ADI1 gene.…”

“…ARD is also implicated in hepatitis C infection 5 , Down’s syndrome (DS)-associated congenital heart defects (DS-CHD) 6 and fecundity in Drosophila. 7 In plants, ARD expression is associated with development and fruit ripening, and so is of great interest to plant biologists. 8 ARD is likely a multi-functional (“moonlighting”) enzyme involved in both regulatory and enzymatic functions.…”

Identification of altered pathways in Down syndrome-associated congenital heart defects using an individualized pathway aberrance score

“…Alternatively, ADI1, in association with Ni 2+ produces formate, carbon monoxide, and 3-methylthiopropionate (Hirano et al, 2005). ADI1 has also been reported to be affected by fecundity, through the regulation of methionine metabolism (Chou et al, 2014). The methionine salvage pathway, also called the MTA cycle, is a sequential pathway comprising six reactions, which is responsible for the creation of methionine from MTA, a byproduct of polyamine biosynthesis in nearly all organisms (Albers, 2009).…”

“…ADI1, a 5'-methylthioadenosine (MTA) cycle enzyme, belongs to the cupin domain superfamily, and has aci-reductone dioxygenase enzymatic activity (Chou et al, 2014). The ADI1 gene, in association with Fe 2+ , produces formate and 2-keto-4-methylthiobutyrate (MTOB), the keto-acid precursor of methionine.…”

Dual chemistry catalyzed by human acireductone dioxygenase

“…A recent clinical study related these two regulatory functions of HsARD, showing that the physical interaction between MT1-MMP and ADI1 leads to suppression of hepatitis C infection and this inhibitory effect could be reversed by ADI1 overexpression (Yeh et al, 2008). ADI1 was also shown to be required for normal Drosophila fecundity (Chou et al, 2014). Under conditions of dietary restriction, the egg production of acireductone dioxygenase 1 (DADI1) deficient flies was reduced compared to that of control flies.…”