AASS (alpha-aminoadipic semialdehyde synthase; LKR/SDH) is a mitochondrial bifunctional enzyme that catalyzes the first two steps of the saccharopine pathway of L-lysine degradation. Its N-terminal lysine-2-oxoglutarate reductase domain (LKR/LOR, EC 1.5.1.8) condenses L-lysine with 2-oxoglutarate using NADPH to form saccharopine. Its C-terminal saccharopine dehydrogenase domain (SDH, EC 1.5.1.9) uses NAD+ to convert saccharopine to alpha-aminoadipic semialdehyde and L-glutamate. The reactions operate in the mitochondrial matrix. Biallelic AASS defects cause hyperlysinemia, often a biochemical phenotype with limited clinical consequences; severe neurological findings can have additional causes. Selective SDH impairment with retained LKR activity produces saccharopine accumulation. Saccharopine toxicity and mitochondrial injury are demonstrated in animal models, while the clinical consequences of this biochemical subtype in humans remain incompletely resolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT inference places AASS in cytoplasm, a compartment that includes mitochondria. The more specific matrix localization is compatible with this conservative ancestral annotation. Reason: QuickGO defines cytoplasm as the cellular contents excluding plasma membrane and nucleus but including other subcellular structures. Mitochondrial localization therefore supports this parent term; breadth alone is not over-annotation. Human mitochondrial GOA evidence and the conserved bifunctional enzyme support the inherited localization. No target-specific loss of this broad localization is evident. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000123605 · PANTHER:PTN000123605 SUPPORTS TRANSFER Ancestral PAINT node recovered from the seeded WITH/FROM field. The inferred function is independently compatible with the human enzyme; the target appearing among experimental descendants is expected, not circular. The complete PAINT tree was not re-curated. Supporting Evidence: Reactome:R-HSA-70938 homotetramer in the mitochondrial matrix |
| GO:0019477 L-lysine catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: AASS directly catalyzes lysine degradation through its two linked catalytic domains. The inherited catabolic-process assignment agrees with human biochemical and genetic evidence. Reason: The PAINT node represents inherited participation in L-lysine catabolism. AASS performs the initial reductive condensation and the following saccharopine oxidation, so this is direct catalysis rather than a downstream phenotype. Human AASS itself contributes experimental descendant evidence to the ancestral inference. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000875308 · PANTHER:PTN000875308 SUPPORTS TRANSFER Ancestral PAINT node recovered from the seeded WITH/FROM field. The inferred function is independently compatible with the human enzyme; the target appearing among experimental descendants is expected, not circular. The complete PAINT tree was not re-curated. Supporting Evidence: PMID:10775527 we propose that AASS catalyzes the first two steps of the major lysine-degradation pathway in human cells and that inactivating mutations in the AASS gene are a cause of hyperlysinemia. PMID:36128717 Another important difference between LYS1 and LOR is that the human protein evolved to use NADPH while yeast uses NADH. |
| GO:0004753 saccharopine dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Saccharopine dehydrogenase activity is a valid parent of both specific AASS reactions. Human LKR/LOR and SDH activities retain this broader inherited molecular function. Reason: The term covers saccharopine cleavage with release of lysine or glutamate and electron-acceptor reduction. QuickGO confirms that GO:0047130 and GO:0047131 are both children of GO:0004753. The human LOR reverse reaction is measurable in vitro, and the SDH reaction releases glutamate; the grouping is therefore correct despite the different physiological directions. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000123605 · PANTHER:PTN000123605 SUPPORTS TRANSFER Ancestral PAINT node recovered from the seeded WITH/FROM field. The inferred function is independently compatible with the human enzyme; the target appearing among experimental descendants is expected, not circular. The complete PAINT tree was not re-curated. Supporting Evidence: PMID:36128717 The rate of the reverse reaction was considerably slower than that of the forward reaction, which is consistent with previous reports [23]. PMID:36128717 SDH then oxidizes saccharopine into 2-aminoapidic semialdehyde and glutamate (EC 1.5.1.9). |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping assigns AASS to mitochondrion, consistent with the transit peptide, human mitochondrial-proteome annotation, and curated matrix reactions. Reason: SL-0173 is the proximate mapping source. Mitochondrion is the appropriate broad compartment. The 1979 abstract does not itself demonstrate localization, so it is not used as direct localization evidence here. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0173 SUPPORTS TRANSFER The UniProt mitochondrial-location vocabulary maps appropriately to mitochondrion and is consistent with the human record and curated matrix reactions. Supporting Evidence: Reactome:R-HSA-70938 homotetramer in the mitochondrial matrix |
| GO:0047130 saccharopine dehydrogenase (NADP+, L-lysine-forming) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined electronic mapping recovers the NADPH-dependent lysine-2-oxoglutarate reductase activity of the N-terminal domain. Reason: The EC and Rhea reaction definitions match the human biochemical function. The lysine-forming wording of GO:0047130 describes the reversible LOR reaction; it does not imply that human AASS normally synthesizes lysine. Propagation Review Root cause: NO FAILURE CORE Sources checked: EC:1.5.1.8 SUPPORTS TRANSFER The EC cofactor and product specificity match this human AASS catalytic domain. RHEA:19373 SUPPORTS TRANSFER Reaction mapping agrees with the independently checked GO definition and human enzyme chemistry. ARBA:ARBA00091576 UNRESOLVED Rule identifier traced from the seed; its complete predicates were not independently audited. The mapped activity is supported independently. UniProtKB:Q99K67 SUPPORTS TRANSFER Mouse Aass carries experimental evidence for this conserved catalytic activity (PMID:10567240); human biochemical evidence independently supports transfer. ensembl:ENSMUSP00000031707 UNRESOLVED Ensembl protein identifier traced from the combined seed; its separate propagation chain was not independently reconstructed. Supporting Evidence: PMID:36128717 Another important difference between LYS1 and LOR is that the human protein evolved to use NADPH while yeast uses NADH. PMID:10775527 we propose that AASS catalyzes the first two steps of the major lysine-degradation pathway in human cells and that inactivating mutations in the AASS gene are a cause of hyperlysinemia. |
| GO:0047131 saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined electronic mapping recovers the NAD+-dependent, glutamate-forming saccharopine dehydrogenase activity of the C-terminal domain. Reason: The reaction releases glutamate and alpha-aminoadipic semialdehyde while reducing NAD+. This is distinct from the lysine-forming reaction catalyzed by the other domain. Propagation Review Root cause: NO FAILURE CORE Sources checked: EC:1.5.1.9 SUPPORTS TRANSFER The EC cofactor and product specificity match this human AASS catalytic domain. RHEA:24520 SUPPORTS TRANSFER Reaction mapping agrees with the independently checked GO definition and human enzyme chemistry. ARBA:ARBA00091572 UNRESOLVED Rule identifier traced from the seed; its complete predicates were not independently audited. The mapped activity is supported independently. UniProtKB:Q99K67 SUPPORTS TRANSFER Mouse Aass carries experimental evidence for this conserved catalytic activity (PMID:10567240); human biochemical evidence independently supports transfer. ensembl:ENSMUSP00000031707 UNRESOLVED Ensembl protein identifier traced from the combined seed; its separate propagation chain was not independently reconstructed. Supporting Evidence: PMID:36128717 SDH then oxidizes saccharopine into 2-aminoapidic semialdehyde and glutamate (EC 1.5.1.9). PMID:10775527 we propose that AASS catalyzes the first two steps of the major lysine-degradation pathway in human cells and that inactivating mutations in the AASS gene are a cause of hyperlysinemia. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000107 | ACCEPT | Summary: The Ensembl Compara mapping transfers mitochondrial-matrix localization from mouse Aass Q99K67. Reason: Live QuickGO tracing recovers mouse GO:0005759 IDA evidence to PMID:18936211. That paper is available here only as an abstract, so its precise localization experiment is not independently reverified. The curator-supported transfer is nevertheless consistent with mammalian mitochondrial enzyme biochemistry, human mitochondrial-proteome evidence and the independently checked Reactome matrix reactions; no compartmental divergence is established. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99K67 SUPPORTS TRANSFER Mouse matrix IDA annotation traces to PMID:18936211 in QuickGO; the detailed assay is inaccessible, but the curated localization and conserved mitochondrial pathway support transfer. ensembl:ENSMUSP00000031707 UNRESOLVED Seeded mouse Ensembl protein identifier; separate mapping details were not independently reconstructed. Supporting Evidence: Reactome:R-HSA-70938 homotetramer in the mitochondrial matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70938 | ACCEPT | Summary: Reactome places the LKR reaction of human AASS in the mitochondrial matrix. Reason: The original Reactome reaction was retrieved and its summary explicitly places the AASS homotetramer in the matrix. This is curated pathway localization, not a new direct human imaging claim. Supporting Evidence: Reactome:R-HSA-70938 homotetramer in the mitochondrial matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70940 | ACCEPT | Summary: Reactome places the SDH reaction of human AASS in the mitochondrial matrix. Reason: The original Reactome reaction was retrieved and its summary explicitly places the AASS homotetramer in the matrix. This is curated pathway localization, not a new direct human imaging claim. Supporting Evidence: Reactome:R-HSA-70940 homotetramer in the mitochondrial matrix |
| GO:0005739 mitochondrion | EXP PMID:463877 Familial hyperlysinemia: enzyme studies, diagnostic methods,... | ACCEPT | Summary: Retain the curator-assigned mitochondrial localization, independently corroborated by human mitochondrial proteomics and matrix pathway evidence. The full 1979 paper remains unavailable. Reason: The 1979 abstract does not document the localization experiment, so this is not an independent verification of its fractionation methods. Nevertheless, mitochondrial localization is clearly correct for AASS: the human MitoCoP supplement identifies Q9UDR5, the human record carries a mitochondrial transit peptide, and both curated Reactome reactions occur in the matrix. Defer to the original experimental curator for this supported compartment while retaining the publication-access caveat; no claim of exclusive mitochondrial localization follows. Supporting Evidence: PMID:463877 saccharopine oxidoreductase was partially purified from human liver and characterized. Reactome:R-HSA-70938 homotetramer in the mitochondrial matrix |
| GO:0047130 saccharopine dehydrogenase (NADP+, L-lysine-forming) activity | EXP PMID:463877 Familial hyperlysinemia: enzyme studies, diagnostic methods,... | ACCEPT | Summary: Human fibroblast enzyme studies report combined deficiency of lysine-ketoglutarate reductase and saccharopine dehydrogenase in familial hyperlysinemia. Reason: The abstract directly supports the reported enzymatic activities and their co-purification. Its limited methods are supplemented by later identification of AASS and human domain biochemistry; the full 1979 paper remains unavailable, so detailed assay conditions are not asserted. Supporting Evidence: PMID:463877 In all instances there was a deficiency in lysine-ketoglutarate reductase, saccharopine dehydrogenase, and saccharopine oxidoreductase activities. PMID:36128717 Another important difference between LYS1 and LOR is that the human protein evolved to use NADPH while yeast uses NADH. |
| GO:0047131 saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity | EXP PMID:463877 Familial hyperlysinemia: enzyme studies, diagnostic methods,... | ACCEPT | Summary: Human fibroblast enzyme studies report combined deficiency of lysine-ketoglutarate reductase and saccharopine dehydrogenase in familial hyperlysinemia. Reason: The abstract directly supports the reported enzymatic activities and their co-purification. Its limited methods are supplemented by later identification of AASS and human domain biochemistry; the full 1979 paper remains unavailable, so detailed assay conditions are not asserted. Supporting Evidence: PMID:463877 In all instances there was a deficiency in lysine-ketoglutarate reductase, saccharopine dehydrogenase, and saccharopine oxidoreductase activities. PMID:36128717 SDH then oxidizes saccharopine into 2-aminoapidic semialdehyde and glutamate (EC 1.5.1.9). |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: Human AASS is present in the published MitoCoP supplementary dataset: Table S1, sheet (B), row 5 lists Q9UDR5, AASS, protein group 11286, MitoCoP=1. Reason: The publisher supplementary workbook was downloaded and the AASS entry independently inspected. Sheet (A), row 5 also records this protein group as identified in the dataset and included in MitoCoP. This directly corroborates the human mitochondrial HTP annotation; it does not by itself establish matrix subcompartment or exclude additional localization. The abstract quote describes the dataset, while the exact supplementary provenance and inspected fields are recorded in the notes. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP) Reactome:R-HSA-70938 homotetramer in the mitochondrial matrix |
| GO:0047130 saccharopine dehydrogenase (NADP+, L-lysine-forming) activity | IMP PMID:10775527 Identification of the alpha-aminoadipic semialdehyde synthas... | ACCEPT | Summary: Human AASS gene identification and an inactivating patient allele support lysine-2-oxoglutarate reductase activity. Reason: The original abstract links the human bifunctional gene to hyperlysinemia and identifies its LYS1-like N-terminal and LYS9-like C-terminal regions. Later human biochemistry and genetic studies corroborate the assignment. The full 2000 paper could not be retrieved, so no uninspected domain-specific kinetic measurements or complete absence of protein are inferred from it. Supporting Evidence: PMID:10775527 we propose that AASS catalyzes the first two steps of the major lysine-degradation pathway in human cells and that inactivating mutations in the AASS gene are a cause of hyperlysinemia. PMID:36128717 Another important difference between LYS1 and LOR is that the human protein evolved to use NADPH while yeast uses NADH. |
| GO:0019477 L-lysine catabolic process | IMP PMID:10775527 Identification of the alpha-aminoadipic semialdehyde synthas... | ACCEPT | Summary: Human AASS gene identification and an inactivating patient allele support direct participation in lysine catabolism. Reason: The original abstract links the human bifunctional gene to hyperlysinemia and identifies its LYS1-like N-terminal and LYS9-like C-terminal regions. Later human biochemistry and genetic studies corroborate the assignment. The full 2000 paper could not be retrieved, so no uninspected domain-specific kinetic measurements or complete absence of protein are inferred from it. Supporting Evidence: PMID:10775527 we propose that AASS catalyzes the first two steps of the major lysine-degradation pathway in human cells and that inactivating mutations in the AASS gene are a cause of hyperlysinemia. PMID:36128717 Another important difference between LYS1 and LOR is that the human protein evolved to use NADPH while yeast uses NADH. |
| GO:0047131 saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity | IMP PMID:10775527 Identification of the alpha-aminoadipic semialdehyde synthas... | ACCEPT | Summary: Human AASS gene identification and an inactivating patient allele support saccharopine dehydrogenase activity. Reason: The original abstract links the human bifunctional gene to hyperlysinemia and identifies its LYS1-like N-terminal and LYS9-like C-terminal regions. Later human biochemistry and genetic studies corroborate the assignment. The full 2000 paper could not be retrieved, so no uninspected domain-specific kinetic measurements or complete absence of protein are inferred from it. Supporting Evidence: PMID:10775527 we propose that AASS catalyzes the first two steps of the major lysine-degradation pathway in human cells and that inactivating mutations in the AASS gene are a cause of hyperlysinemia. PMID:36128717 SDH then oxidizes saccharopine into 2-aminoapidic semialdehyde and glutamate (EC 1.5.1.9). |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | UNDECIDED | Summary: ISS transfer from Drosophila dLKR/SDH (Q9VLX0), with experimentally grounded donor evidence in PMID:18695041. Conservation of this moonlighting function in human AASS remains unresolved. Reason: The donor study directly demonstrates ecdysone-dependent repression of dronc/ark transcription in Drosophila, including promoter occupancy and mutant effects. Shared LKR and SDH domains and the reported 51% identity make a conserved moonlighting interaction plausible. However, receptor recruitment and promoter context were tested in the EcR/Usp system, and the relevant interaction surfaces have not been mapped onto human AASS. Sequence homology alone does not resolve this contextual function. No demonstrated human loss or prohibition on dual localization is claimed. The reported 51% identity/71% similarity is not treated as proof of conservation of the non-catalytic contact surface. Conversely, missing human characterization does not itself establish a failed ISS transfer. UNDECIDED records this biological uncertainty after assessment, not a failure to read the donor paper. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9VLX0 · Drosophila melanogaster LKRSDH UNRESOLVED PMID:18695041 directly supports repression of fly EcR/Usp-responsive dronc and ark transcription. The effect persists with a catalytically inactive mutant and is absent from the tested BR-C reporter. This establishes a receptor-context-dependent source process, not an automatic consequence of conserved lysine catabolism. Whether human AASS participates in an analogous transcriptional context remains unresolved; a human loss of this moonlighting role has not been demonstrated. Supporting Evidence: PMID:18695041 dLKR/SDH binds histones H3 and H4 and suppresses ecdysone-mediated transcription of cell death genes by inhibiting histone H3R17me2 mediated by the Drosophila arginine methyl transferase CARMER. PMID:18695041 dLKR/SDH is 51% identical and 71% similar to mouse and human LKR/SDH. |
| GO:0003714 transcription corepressor activity | ISS GO_REF:0000024 | UNDECIDED | Summary: ISS transfer from Drosophila dLKR/SDH (Q9VLX0), with experimentally grounded donor evidence in PMID:18695041. Conservation of this moonlighting function in human AASS remains unresolved. Reason: The donor has genuine corepressor activity: its LKR region associates with histones while its SDH region associates with EcR-B1, and repression is separable from metabolic catalysis. Human AASS retains both domains, so conservation is plausible. The human counterparts of the donor receptor-contact and histone-contact surfaces, nuclear recruitment, and repression have not been established by the studies examined. This prevents a confident decision on this ISS transfer without demonstrating functional divergence. The reported 51% identity/71% similarity is not treated as proof of conservation of the non-catalytic contact surface. Conversely, missing human characterization does not itself establish a failed ISS transfer. UNDECIDED records this biological uncertainty after assessment, not a failure to read the donor paper. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9VLX0 · Drosophila melanogaster LKRSDH UNRESOLVED The fly source binds EcR-B1 through its SDH region (residues 618-928 retain binding; truncation to 803 diminishes it) and represses the receptor reporter independently of metabolic catalysis. Human AASS retains the domain, but the corresponding cofactor interaction and recruitment mechanism have not been established in the sources examined. This is an unresolved transfer, not demonstrated absence of a human corepressor function. Supporting Evidence: PMID:18695041 dLKR/SDH binds histones H3 and H4 and suppresses ecdysone-mediated transcription of cell death genes by inhibiting histone H3R17me2 mediated by the Drosophila arginine methyl transferase CARMER. PMID:18695041 dLKR/SDH is 51% identical and 71% similar to mouse and human LKR/SDH. |
| GO:0004754 saccharopine dehydrogenase (NAD+, L-lysine-forming) activity | ISS GO_REF:0000024 | MODIFY | Summary: The NAD-dependent lysine-forming term does not capture established human LKR/LOR cofactor specificity. The appropriate human term is NADP-dependent GO:0047130, already represented by other annotations. Reason: QuickGO distinguishes GO:0004754 (NAD+/NADH, lysine and 2-oxoglutarate) from GO:0047130 (NADP+/NADPH, the same products). The donor experiment measures NADH oxidation but does not establish that fly LKR excludes NADPH. Human LOR biochemical assays and the 2022 discussion independently support NADPH dependence. Physiological reaction direction is not the objection: both directions are measurable in vitro. Replacing this ISS assertion with GO:0047130 means retiring or reconciling the redundant GO:0004754 row into the already supported GO:0047130 annotation, not adding a fourth duplicate or a NEW annotation. GO:0047131 would instead switch to the other AASS domain. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: UniProtKB:Q9VLX0 · Drosophila melanogaster LKRSDH SUPPORTS SOURCE BUT NOT TARGET The donor assay demonstrates NADH oxidation, without establishing exclusive fly cofactor specificity. The human NADP-dependent LOR function is independently supported, so transfer of this specifically NAD-dependent term is unsafe even though the proteins share a catalytic domain. This does not infer a general loss of fly moonlighting functions. Proposed replacements: saccharopine dehydrogenase (NADP+, L-lysine-forming) activity Supporting Evidence: PMID:36128717 Another important difference between LYS1 and LOR is that the human protein evolved to use NADPH while yeast uses NADH. PMID:36128717 The rate of the reverse reaction was considerably slower than that of the forward reaction, which is consistent with previous reports [23]. PMID:18695041 By using lysine as a substrate, we measured oxidation of NADH to NAD+ and observed a time-dependent decrease in NADH, implying that the full-length protein is enzymatically active (Fig. 2 A). PMID:36128717 A defect in the mitochondrial biosynthesis of NADP+ leads to hyperlysinemia demonstrating that in man and mouse NADPH cannot be replaced by NADH [28–31]. |
| GO:0005829 cytosol | ISS GO_REF:0000024 | UNDECIDED | Summary: ISS transfer from Drosophila dLKR/SDH (Q9VLX0), with experimentally grounded donor evidence in PMID:18695041. Conservation of this localization in human AASS remains unresolved. Reason: Fractionation and tagged-protein experiments establish cytosolic fly dLKR/SDH. Human AASS carries a mitochondrial targeting sequence and has mitochondrial evidence, but those facts do not exclude a smaller or conditional cytosolic pool. The donor has dynamic localization and no experimentally mapped targeting mechanism whose conservation can be judged here. Transfer of this specific extra-mitochondrial distribution remains unresolved, rather than contradicted. The live fly UniProt record also carries mitochondrial-location and transit-peptide annotations (electronic evidence, no experimentally mapped cleavage site). The donor fractionation does not separately assay mitochondria. Consequently neither absence of fly mitochondrial targeting nor exclusive fly cytosolic/nuclear localization has been established. These checks do not resolve conservation of an additional human pool. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9VLX0 · Drosophila melanogaster LKRSDH UNRESOLVED The fly source is detected in the cytoplasmic fraction using DRONC/DRICE controls and in tagged-protein imaging. Fig. 1F does not assay a dedicated mitochondrial fraction or mitochondrial marker. Current Q9VLX0 has electronic mitochondrial and transit-peptide annotations; therefore donor absence of mitochondrial targeting cannot justify rejection. Stable extra-mitochondrial localization in human AASS is neither established nor excluded by the mitochondrial evidence. Supporting Evidence: PMID:18695041 dLKR/SDH was readily detectable in the cytosol of both untreated and ecdysone-treated cells. PMID:18695041 dLKR/SDH is 51% identical and 71% similar to mouse and human LKR/SDH. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | UNDECIDED | Summary: ISS transfer from Drosophila dLKR/SDH (Q9VLX0), with experimentally grounded donor evidence in PMID:18695041. Conservation of this localization in human AASS remains unresolved. Reason: The donor study detects nuclear dLKR/SDH in fractionation, tagged-protein localization and promoter assays. The authors report no nuclear localization signal and discuss possible partner-dependent shuttling, leaving the targeting determinant uncertain. Human AASS retains both catalytic domains but has established mitochondrial targeting. That does not prove absence from nuclei, and the conservation of the donor recruitment mechanism cannot be resolved from domain homology alone. The live fly UniProt record also carries mitochondrial-location and transit-peptide annotations (electronic evidence, no experimentally mapped cleavage site). The donor fractionation does not separately assay mitochondria. Consequently neither absence of fly mitochondrial targeting nor exclusive fly cytosolic/nuclear localization has been established. These checks do not resolve conservation of an additional human pool. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9VLX0 · Drosophila melanogaster LKRSDH UNRESOLVED The fly source has nuclear fractionation, tagged imaging and promoter recruitment evidence. HP1-beta marks the nuclear fraction; the study does not test a mitochondrial fraction. The authors describe no nuclear localization signal and only a putative export signal, with partner-mediated recruitment proposed. Electronic mitochondrial/transit-peptide annotations on Q9VLX0 defeat a simple fly-versus-human targeting dichotomy, but do not establish conservation of nuclear recruitment. Supporting Evidence: PMID:18695041 dLKR/SDH was also seen in nuclear extracts, and the protein levels appeared to be dynamic upon ecdysone treatment, decreasing at 10–30 min of treatment and increasing by 1 h (Fig. 1 F). PMID:18695041 dLKR/SDH is 51% identical and 71% similar to mouse and human LKR/SDH. |
| GO:0042393 histone binding | ISS GO_REF:0000024 | UNDECIDED | Summary: ISS transfer from Drosophila dLKR/SDH (Q9VLX0), with experimentally grounded donor evidence in PMID:18695041. Conservation of this moonlighting function in human AASS remains unresolved. Reason: Direct fly histone H3/H4 binding and inhibition of H3R17 methylation are supported by the full donor paper. Histones and the AASS LKR domain are conserved, making transfer plausible; however, the binding surface has not been established at residue resolution or tested in the human protein in the studies examined. Cofactor differences in the metabolic reaction do not by themselves invalidate this separate binding activity. The evidence establishes the donor function but does not settle its transfer. The reported 51% identity/71% similarity is not treated as proof of conservation of the non-catalytic contact surface. Conversely, missing human characterization does not itself establish a failed ISS transfer. UNDECIDED records this biological uncertainty after assessment, not a failure to read the donor paper. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9VLX0 · Drosophila melanogaster LKRSDH UNRESOLVED Fly LKR binds histones H3/H4, with H3 binding favored for an unmodified tail and inhibition of CARMER-mediated H3R17 methylation. Human LKR and histones are conserved, but residue-level histone-contact determinants were not resolved in the source. Neither catalytic-domain similarity nor metabolic cofactor differences settle conservation of this separate binding interaction, leaving the transfer classification unresolved. Supporting Evidence: PMID:18695041 dLKR/SDH binds histones H3 and H4 and suppresses ecdysone-mediated transcription of cell death genes by inhibiting histone H3R17me2 mediated by the Drosophila arginine methyl transferase CARMER. PMID:18695041 dLKR/SDH is 51% identical and 71% similar to mouse and human LKR/SDH. |
| GO:0005739 mitochondrion | TAS PMID:10567240 Lysine degradation through the saccharopine pathway in mamma... | ACCEPT | Summary: The original author statement concerns the mouse bifunctional enzyme and proposes mitochondrial localization. Reason: Retain this mammalian author-statement evidence in the context of independent human mitochondrial-proteome annotation and curated matrix reactions. The mouse abstract says likely mitochondrial; it is not a direct human localization assay. Starvation induction in that paper is likewise mouse evidence. Supporting Evidence: PMID:10567240 the bifunctional enzyme is likely to be a mitochondrial protein. |
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Download this section (compressed HTML)Q: Are the histone-contact and receptor-recruitment surfaces responsible for Drosophila dLKR/SDH moonlighting conserved and functional in human AASS, and can endogenous human AASS access a nuclear or stable cytosolic pool?
Q: How do genetically resolved human selective SDH defects, saccharopine concentrations and clinical outcomes compare with the severe phenotypes of selective SDH mutations in mouse and worm models?
Q: Do the allosteric mechanisms reported in the 2026 human AASS preprint operate at endogenous metabolite concentrations in mitochondria?
Experiment: Combine endogenous AASS tagging and validated subcellular fractionation in human cells with histone-binding and receptor-recruitment assays. Compare mitochondrial targeting and the fly interaction domains without inferring loss of function from the mitochondrial targeting sequence alone.
Experiment: Measure LKR and SDH activities separately, together with lysine and saccharopine, in genetically characterized patient cells to distinguish combined deficiency from a selective second-step block.
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