scully (scu; FlyBase FBgn0016976; CG7113) is the Drosophila melanogaster ortholog of human HSD17B10 (17-beta-hydroxysteroid dehydrogenase type 10 / 3-hydroxyacyl-CoA dehydrogenase type 2 / MRPP2), a mitochondrial member of the short-chain dehydrogenase/reductase (SDR) superfamily. It is a multifunctional, moonlighting enzyme with three distinct roles. (1) As an NAD+-dependent (3S)-3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35) it can carry out the third step of mitochondrial fatty acid beta-oxidation for short/medium-chain substrates and the analogous branched-chain step (3-hydroxy-2-methylbutyryl-CoA) of isoleucine catabolism. Because Drosophila lacks a clean ortholog of the classical type-I HADH1/SCHAD (the fly genes named Had1/Had2 are instead CRYL1 orthologs), scully is the fly enzyme covering this type-II 3-hydroxyacyl-CoA dehydrogenase niche. (2) As a broad-specificity hydroxysteroid dehydrogenase (17-beta-HSD10) it oxidizes 17-beta-OH, 3-alpha-OH, 20-beta-OH and 21-OH groups of steroids and 7-beta-OH groups of bile acids, linking it to steroid hormone and, in the fly, ecdysone metabolism; scully is essential for development. (3) As the MRPP2 subunit of the mitochondrial protein-only ribonuclease P (mt:RNase P) complex it is required for 5'-end processing of mitochondrial tRNAs; loss of scully causes aberrant mt-tRNA processing and lethality. The mature protein is a homotetramer with one NAD(H) per subunit; the functional pools relevant to fatty-acid oxidation and to RNase P reside in the mitochondrial matrix (an earlier overexpression study reported a cytosolic pattern for the fly protein, attributed to an N-terminal difference from the human mitochondrial-targeted form).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004303 estradiol 17-beta-dehydrogenase [NAD(P)+] activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred estradiol 17-beta-dehydrogenase activity, a substrate-specific hydroxysteroid dehydrogenase activity of the HSD17B10 family. Experimentally supported for the fly enzyme (PMID:12917011), but one of several steroid substrates of the broad-specificity 17-beta-HSD activity. Reason: A genuine but substrate-specific steroid activity subsumed by the core 17-beta-hydroxysteroid dehydrogenase activity (GO:0044594); retained as non-core. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred mitochondrial localization. Correct compartment but less specific than the mitochondrial matrix, where the RNase P complex and beta-oxidation enzymes act. Reason: Mitochondrion is correct; the more specific mitochondrial matrix (GO:0005759) is the core location annotation. |
| GO:0006631 fatty acid metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred role in fatty acid metabolism, matching scully's (3S)-3-hydroxyacyl-CoA dehydrogenase activity in the beta-oxidation spiral. Independently supported experimentally (PMID:12917011). Reason: A core biological process for scully via its 3-hydroxyacyl-CoA dehydrogenase activity. |
| GO:0008209 androgen metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred androgen metabolism, reflecting the broad steroid substrate range of the 17-beta-HSD10 family. Androgens are not endogenous Drosophila steroids; this reflects the enzyme's in-vitro substrate promiscuity rather than a fly physiological role. Reason: Reflects broad hydroxysteroid dehydrogenase substrate range; non-core for the fly (the endogenous steroid context is ecdysteroid, not vertebrate androgens). |
| GO:0008210 estrogen metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred estrogen metabolism from the 17-beta-HSD substrate range. As for androgens, estrogens are not endogenous Drosophila steroids; this is in-vitro substrate capacity, not a fly physiological pathway. Reason: Broad steroid substrate capacity; non-core for the fly (no endogenous estrogen pathway). |
| GO:0003857 (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the EC 1.1.1.35 (3S)-3-hydroxyacyl-CoA dehydrogenase activity. This is a core molecular function of scully (the type-II, HSD17B10-class enzyme), independently confirmed by direct enzymatic assay (PMID:12917011). Reason: Core molecular function; the electronic call matches the experimentally demonstrated (3S)-3-hydroxyacyl-CoA dehydrogenase activity and the beta-oxidation step-3 role. Supporting Evidence: PMID:12917011 In addition to the known hydroxyacyl-CoA dehydrogenase |
| GO:0004022 alcohol dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | MARK AS OVER ANNOTATED | Summary: RHEA/EC-mapping electronic annotation to the generic alcohol dehydrogenase (NAD+) activity. scully is a specific hydroxyacyl-CoA / hydroxysteroid dehydrogenase, not a generic ethanol-type alcohol dehydrogenase; this over-general term does not describe its actual function. Reason: Uninformative over-general term arising from automated Rhea mapping; the informative activities are the specific 3-hydroxyacyl-CoA and 17-beta-hydroxysteroid dehydrogenase functions. |
| GO:0004303 estradiol 17-beta-dehydrogenase [NAD(P)+] activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic duplicate of the estradiol 17-beta-dehydrogenase activity; substrate-specific hydroxysteroid activity of the 17-beta-HSD10 enzyme. Reason: Substrate-specific steroid activity subsumed by the core 17-beta-hydroxysteroid dehydrogenase activity (GO:0044594). |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic (UniProt subcellular-location) mitochondrion annotation. Correct but less specific than the mitochondrial matrix. Reason: Correct compartment; the mitochondrial matrix (GO:0005759) is the core location. |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation to the parent oxidoreductase (CH-OH donor, NAD(P) acceptor) class. Correct but a high-level parent of scully's specific dehydrogenase activities. Reason: Accurate parent term subsumed by the specific 3-hydroxyacyl-CoA and 17-beta-hydroxysteroid dehydrogenase activities. |
| GO:0044594 17-beta-hydroxysteroid dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | ACCEPT | Summary: RHEA-based electronic assignment of 17-beta-hydroxysteroid dehydrogenase activity, the defining steroid-oxidoreductase function of the HSD17B10 family. Directly confirmed for the fly enzyme by enzymatic assay (PMID:12917011). Reason: A core molecular function of scully (17-beta-HSD10); the electronic call matches the experimentally demonstrated hydroxysteroid dehydrogenase activity. Supporting Evidence: PMID:12917011 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyse the conversion of 17beta-OH (-hydroxy)/17-oxo groups of steroids |
| GO:0006550 L-isoleucine catabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Orthology-based transfer of the isoleucine catabolic role. HSD17B10-family enzymes carry the branched-chain 3-hydroxy-2-methylbutyryl-CoA dehydrogenase step of isoleucine degradation, so this is a genuine but secondary branched-chain-amino-acid role alongside the straight-chain fatty-acid role. Reason: Real branched-chain (isoleucine) catabolic role via the 3-hydroxy-2-methylbutyryl-CoA dehydrogenase activity; peripheral to the core fatty-acid and steroid functions. |
| GO:0044594 17-beta-hydroxysteroid dehydrogenase (NAD+) activity | IDA PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | ACCEPT | Summary: Direct-assay demonstration of 17-beta-hydroxysteroid dehydrogenase activity for the purified Drosophila enzyme, together with a broad panel of additional hydroxysteroid/bile-acid specificities. Reason: Core, experimentally established steroid-oxidoreductase molecular function of scully. Supporting Evidence: PMID:12917011 oxidize the 20beta-OH and 21-OH groups in C21 steroids |
| GO:0047015 3-hydroxy-2-methylbutyryl-CoA dehydrogenase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Orthology-based transfer of the branched-chain 3-hydroxy-2-methylbutyryl-CoA dehydrogenase activity, the isoleucine-pathway specialization of HSD17B10. A specific substrate variant of the general 3-hydroxyacyl-CoA dehydrogenase activity. Reason: Genuine branched-chain substrate activity underpinning the isoleucine-catabolism role; non-core relative to the general (3S)-3-hydroxyacyl-CoA dehydrogenase activity. |
| GO:0005759 mitochondrial matrix | IDA PMID:27131785 Loss of the mitochondrial protein-only ribonuclease P comple... | ACCEPT | Summary: Direct-assay localization to the mitochondrial matrix, consistent with scully acting there as part of the mt:RNase P complex and as a matrix dehydrogenase. Reason: The specific, core compartment where scully's RNase P and dehydrogenase functions operate. Supporting Evidence: PMID:27131785 responsible for 5'-end maturation and is comprised of three |
| GO:0005759 mitochondrial matrix | IC PMID:34199774 Loss of Individual Mitochondrial Ribonuclease P Complex Prot... | ACCEPT | Summary: Curator-inferred mitochondrial matrix localization from the mt:RNase P in-vivo processing study. Concordant with the IDA matrix annotation. Reason: Core matrix localization, consistent across independent studies of the RNase P complex. Supporting Evidence: PMID:34199774 responsible for cleaving and processing the 5'-end of mt:tRNAs |
| GO:0097745 mitochondrial tRNA 5'-end processing | IMP PMID:34199774 Loss of Individual Mitochondrial Ribonuclease P Complex Prot... | ACCEPT | Summary: Direct experimental (IMP) evidence that scully, as the MRPP2 subunit of mt:RNase P, is required for 5'-end processing of mitochondrial tRNAs; its loss disrupts mt-tRNA maturation in vivo. Reason: A core (indeed essential) biological process for scully - the mt:RNase P role that underlies the lethality of scully loss. Supporting Evidence: PMID:34199774 responsible for cleaving and processing the 5'-end of mt:tRNAs |
| GO:0140040 mitochondrial polycistronic RNA processing | IMP PMID:34199774 Loss of Individual Mitochondrial Ribonuclease P Complex Prot... | KEEP AS NON CORE | Summary: IMP annotation for the broader mitochondrial polycistronic transcript processing, of which the RNase P 5'-tRNA cleavage (the "tRNA punctuation" model) is a part. Reason: A more general framing of the mt:RNase P processing role; the specific mitochondrial tRNA 5'-end processing term is the core biological-process annotation. |
| GO:0003857 (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | EXP PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | ACCEPT | Summary: Experimental demonstration of (3S)-3-hydroxyacyl-CoA dehydrogenase activity for the purified Drosophila enzyme, establishing the beta-oxidation step-3 catalytic capacity directly. Reason: Core molecular function, experimentally established; the fly enzyme covering the type-II 3-hydroxyacyl-CoA dehydrogenase niche. Supporting Evidence: PMID:12917011 In addition to the known hydroxyacyl-CoA dehydrogenase |
| GO:0004303 estradiol 17-beta-dehydrogenase [NAD(P)+] activity | EXP PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | KEEP AS NON CORE | Summary: Experimental estradiol 17-beta-dehydrogenase activity, one of the measured steroid substrate specificities of the fly 17-beta-HSD10. Reason: Substrate-specific steroid activity subsumed by the core 17-beta-hydroxysteroid dehydrogenase activity (GO:0044594). |
| GO:0005739 mitochondrion | EXP PMID:34199774 Loss of Individual Mitochondrial Ribonuclease P Complex Prot... | KEEP AS NON CORE | Summary: Experimental mitochondrial localization from the in-vivo mt:RNase P study. Correct but less specific than the matrix annotation. Reason: Correct compartment; mitochondrial matrix (GO:0005759) is the core location. |
| GO:0047035 testosterone dehydrogenase (NAD+) activity | EXP PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | KEEP AS NON CORE | Summary: Experimentally measured testosterone (17-beta-OH) dehydrogenase activity, a specific steroid substrate of the broad 17-beta-HSD10 activity. Reason: Substrate-specific steroid activity subsumed by the core 17-beta-hydroxysteroid dehydrogenase activity; testosterone is not an endogenous fly steroid. |
| GO:0106282 isoursodeoxycholate 7-beta-dehydrogenase (NAD+) activity | EXP PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | KEEP AS NON CORE | Summary: Experimentally measured 7-beta-OH dehydrogenase activity on isoursodeoxycholic acid, reflecting the enzyme's bile-acid substrate promiscuity (a wide hydrophobic substrate cleft). Reason: Bile-acid substrate-specific activity reflecting broad substrate range; non-core. Supporting Evidence: PMID:12917011 7beta-OH dehydrogenases of ursodeoxycholic or isoursodeoxycholic acid |
| GO:0106283 ursodeoxycholate 7-beta-dehydrogenase (NAD+) activity | EXP PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | KEEP AS NON CORE | Summary: Experimentally measured 7-beta-OH dehydrogenase activity on ursodeoxycholic acid, another bile-acid substrate of the broad-specificity enzyme. Reason: Bile-acid substrate-specific activity reflecting broad substrate range; non-core. Supporting Evidence: PMID:12917011 7beta-OH dehydrogenases of ursodeoxycholic or isoursodeoxycholic acid |
| GO:0005739 mitochondrion | NAS PMID:27131785 Loss of the mitochondrial protein-only ribonuclease P comple... | KEEP AS NON CORE | Summary: Non-traceable author statement of mitochondrial localization from the mt:RNase P study; correct but less specific than the matrix. Reason: Correct compartment; mitochondrial matrix is the core location. |
| GO:0030678 mitochondrial ribonuclease P complex | NAS PMID:27131785 Loss of the mitochondrial protein-only ribonuclease P comple... | ACCEPT | Summary: scully is a subunit (MRPP2) of the three-protein mitochondrial protein-only RNase P complex (MRPP1/MRPP2/MRPP3) that performs 5'-tRNA maturation. Reason: Core complex membership; scully's essential mt:RNase P role is exerted as part of this complex. Supporting Evidence: PMID:27131785 responsible for 5'-end maturation and is comprised of three |
| GO:0097745 mitochondrial tRNA 5'-end processing | NAS PMID:27131785 Loss of the mitochondrial protein-only ribonuclease P comple... | ACCEPT | Summary: Author statement that the mt:RNase P complex containing scully performs 5'-end maturation of mitochondrial tRNAs; concordant with the IMP evidence. Reason: Core biological process (mt:RNase P 5'-tRNA processing), consistent across studies. Supporting Evidence: PMID:27131785 responsible for 5'-end maturation and is comprised of three |
| GO:0030678 mitochondrial ribonuclease P complex | IDA PMID:27131785 Loss of the mitochondrial protein-only ribonuclease P comple... | ACCEPT | Summary: Direct-assay evidence for scully as a component of the mitochondrial RNase P complex. Reason: Core complex membership, directly demonstrated. Supporting Evidence: PMID:27131785 responsible for 5'-end maturation and is comprised of three |
| GO:0090646 mitochondrial tRNA processing | IMP PMID:27131785 Loss of the mitochondrial protein-only ribonuclease P comple... | ACCEPT | Summary: Mutant-phenotype evidence that loss of scully causes aberrant mitochondrial tRNA processing and lethality, establishing its requirement for mt-tRNA maturation. Reason: Core biological process; the general mt-tRNA processing role realized through the specific 5'-end processing step. Supporting Evidence: PMID:27131785 tRNA processing and lethality in Drosophila |
| GO:0005739 mitochondrion | HDA PMID:19317464 Mapping organelle proteins and protein complexes in Drosophi... | KEEP AS NON CORE | Summary: High-throughput organelle-proteomics localization of scully to the mitochondrion, corroborating the matrix and RNase P evidence. Reason: Correct compartment from proteomics; mitochondrial matrix is the specific core location. |
| GO:0006631 fatty acid metabolic process | IDA PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | ACCEPT | Summary: Direct-assay support for a role in fatty acid metabolism via the demonstrated 3-hydroxyacyl-CoA dehydrogenase activity. Reason: Core biological process for scully through its 3-hydroxyacyl-CoA dehydrogenase activity. Supporting Evidence: PMID:12917011 In addition to the known hydroxyacyl-CoA dehydrogenase |
| GO:0006637 acyl-CoA metabolic process | IDA PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | KEEP AS NON CORE | Summary: Acyl-CoA metabolic process framing of the 3-hydroxyacyl-CoA dehydrogenase activity (its substrates and products are acyl-CoA thioesters). Reason: A more general process term for the same catalytic role captured by fatty acid metabolic process; retained as non-core. |
| GO:0008202 steroid metabolic process | IDA PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | ACCEPT | Summary: Direct-assay support for a role in steroid metabolism via the demonstrated hydroxysteroid dehydrogenase activities; in the fly this connects to ecdysteroid metabolism. Reason: Core biological process paired with the 17-beta-hydroxysteroid dehydrogenase molecular function. Supporting Evidence: PMID:12917011 oxidize the 20beta-OH and 21-OH groups in C21 steroids |
| GO:0008205 ecdysone metabolic process | IDA PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | KEEP AS NON CORE | Summary: Ecdysone (insect steroid hormone) metabolism, the endogenous Drosophila steroid context for scully's hydroxysteroid dehydrogenase activity, consistent with its essential developmental role. Reason: Fly-relevant steroid-metabolism role via the core 17-beta-HSD activity; retained as a substrate/context-specific (non-core) process, deferring to the curator's IDA assignment. |
| GO:0008209 androgen metabolic process | IDA PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | KEEP AS NON CORE | Summary: Androgen dehydrogenase activity measured in vitro; androgens are not endogenous fly steroids, so this reflects substrate capacity rather than a Drosophila physiological pathway. Reason: In-vitro steroid substrate capacity; non-core for the fly. |
| GO:0008210 estrogen metabolic process | IDA PMID:12917011 Expanded substrate screenings of human and Drosophila type 1... | KEEP AS NON CORE | Summary: Estrogen dehydrogenase activity measured in vitro; as for androgens, not an endogenous fly steroid pathway. Reason: In-vitro steroid substrate capacity; non-core for the fly. |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Orthology-based mitochondrion localization. Correct but less specific than the mitochondrial matrix; note an earlier overexpression study reported a cytosolic pattern for the fly protein, but the functional (RNase P, matrix-proteomics) evidence supports mitochondrial matrix. Reason: Correct compartment; mitochondrial matrix is the core location. |
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Download this section (compressed HTML)Q: Which of scully's three roles - 3-hydroxyacyl-CoA dehydrogenase, 17-beta-hydroxysteroid dehydrogenase, or the structural MRPP2/mt:RNase P subunit - is responsible for the lethality of scully-null Drosophila, and can catalytically-dead but assembly-competent alleles separate the enzymatic from the RNA-processing functions?
Q: Given that Drosophila lacks a classical type-I HADH1/SCHAD, how much of mitochondrial short/medium-chain 3-hydroxyacyl-CoA dehydrogenase flux in vivo is carried by scully versus the MTP (Mtpalpha) complex?
Experiment: Assay purified recombinant scully for (3S)-3-hydroxyacyl-CoA dehydrogenase kinetics across a short/medium-chain acyl-CoA series (C4-C12) to define its beta-oxidation substrate range relative to the MTP long-chain enzyme.
Hypothesis: scully preferentially handles short/medium-chain 3-hydroxyacyl-CoA substrates, complementing the long-chain specificity of the MTP complex.
Experiment: Generate separation-of-function scully alleles (catalytically inactive vs RNase-P-assembly defective) and test rescue of the null lethality to dissect the essential moonlighting role.
Hypothesis: The mt:RNase P (MRPP2) structural role, not the dehydrogenase activity, is the essential function underlying scully-null lethality.
scully (scu) encodes a mitochondrial protein that is part of a three protein complex responsible for cleaving the 5'-end of mitochondrial tRNAs. scu product forms a sub-complex with the protein encoded by rswl. This sub-complex binds the tRNA and recruits the metallonuclease encoded by mldr, which is responsible for cleaving the phosphodiester backbone of the RNA. Loss of scu results in lethality and aberrantly processed mtDNA transcripts.
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