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.
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