Aldh7a1 (antiquitin, alpha-aminoadipic semialdehyde dehydrogenase) is an NAD+-dependent member of the aldehyde dehydrogenase superfamily. It oxidizes L-2-aminoadipate 6-semialdehyde (alpha-AASA), which is in equilibrium with delta1-piperideine-6-carboxylate (P6C), to L-2-aminoadipate. This is the step at which the saccharopine and pipecolate routes of L-lysine degradation converge. Mice lacking Aldh7a1 accumulate P6C, alpha-AASA and pipecolate in brain and liver and develop pyridoxine-responsive seizures on a high-lysine diet, which models human pyridoxine-dependent epilepsy. Alternative transcripts encode a mitochondrial isoform with an N-terminal presequence and a non-mitochondrial isoform, and in mouse tissues the protein is found in mitochondria, cytosol and nuclei. By orthology to the human enzyme (a homotetramer), it is expected to also oxidize betaine aldehyde and lipid-peroxidation-derived and medium-chain aldehydes. In human cells, a stress-recruited membrane pool generates NADH that restrains vesicle transport and supports FSP1-mediated ferroptosis resistance. The AMPK phosphorylation site that controls this recruitment in human is not conserved in mouse, and the membrane role has not been tested in mouse.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Golgi membrane (stress-recruited pool, inferred from human). Reason: In human cells, the non-mitochondrial ALDH7A1 isoform is recruited to Golgi and other membranes, where it generates NADH; AMPK phosphorylation at Ser130 (Ser102 in isoform-2 numbering) promotes this (PMID:31492851, PMID:40233740). PAINT propagated this location to PTN000192435, which includes mouse. However, no mouse experiment shows the membrane pool, and mouse fractionation found no microsomal ALDH7A1 (PMID:20207735). In addition, the AMPK site is Arg130 in mouse and rat. Membrane association may still occur by other means, so the location is kept as a non-core inference and should not be used as an experimentally established mouse fact. Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0000139 Golgi membrane | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Golgi membrane (stress-recruited pool, inferred from human). Reason: In human cells, the non-mitochondrial ALDH7A1 isoform is recruited to Golgi and other membranes, where it generates NADH; AMPK phosphorylation at Ser130 (Ser102 in isoform-2 numbering) promotes this (PMID:31492851, PMID:40233740). PAINT propagated this location to PTN000192435, which includes mouse. However, no mouse experiment shows the membrane pool, and mouse fractionation found no microsomal ALDH7A1 (PMID:20207735). In addition, the AMPK site is Arg130 in mouse and rat. Membrane association may still occur by other means, so the location is kept as a non-core inference and should not be used as an experimentally established mouse fact. Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0000139 Golgi membrane | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Golgi membrane (stress-recruited pool, inferred from human). Reason: In human cells, the non-mitochondrial ALDH7A1 isoform is recruited to Golgi and other membranes, where it generates NADH; AMPK phosphorylation at Ser130 (Ser102 in isoform-2 numbering) promotes this (PMID:31492851, PMID:40233740). PAINT propagated this location to PTN000192435, which includes mouse. However, no mouse experiment shows the membrane pool, and mouse fractionation found no microsomal ALDH7A1 (PMID:20207735). In addition, the AMPK site is Arg130 in mouse and rat. Membrane association may still occur by other means, so the location is kept as a non-core inference and should not be used as an experimentally established mouse fact. Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0000139 Golgi membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Golgi membrane (stress-recruited pool, inferred from human). Reason: In human cells, the non-mitochondrial ALDH7A1 isoform is recruited to Golgi and other membranes, where it generates NADH; AMPK phosphorylation at Ser130 (Ser102 in isoform-2 numbering) promotes this (PMID:31492851, PMID:40233740). PAINT propagated this location to PTN000192435, which includes mouse. However, no mouse experiment shows the membrane pool, and mouse fractionation found no microsomal ALDH7A1 (PMID:20207735). In addition, the AMPK site is Arg130 in mouse and rat. Membrane association may still occur by other means, so the location is kept as a non-core inference and should not be used as an experimentally established mouse fact. Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0000139 Golgi membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Golgi membrane (stress-recruited pool, inferred from human). Reason: In human cells, the non-mitochondrial ALDH7A1 isoform is recruited to Golgi and other membranes, where it generates NADH; AMPK phosphorylation at Ser130 (Ser102 in isoform-2 numbering) promotes this (PMID:31492851, PMID:40233740). PAINT propagated this location to PTN000192435, which includes mouse. However, no mouse experiment shows the membrane pool, and mouse fractionation found no microsomal ALDH7A1 (PMID:20207735). In addition, the AMPK site is Arg130 in mouse and rat. Membrane association may still occur by other means, so the location is kept as a non-core inference and should not be used as an experimentally established mouse fact. Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Broad NAD+-dependent aldehyde dehydrogenase activity on non-lysine aldehydes, including lipid-peroxidation-derived and medium-chain aldehydes. Reason: Purified human ALDH7A1 oxidizes several aldehyde substrates (PMID:20207735). Mouse is the 1:1 ortholog with the active site conserved. No experiment in mouse tests this directly. The inference rests on orthology to human ALDH7A1 (88.3% identity, conserved catalytic Glu296/Cys330, shared PAINT node PTN000192435 despite the PANTHER SF1/SF5 split, which looks like a classification artifact). The PAINT node carries GO:0004029 one level up (PTN000192422, with human as seed), so the activity is inferred for the whole family. This is accepted as a core but inferred activity; mouse-specific kinetics are lacking. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md human P49419 | 0.883 (539 columns) | E296 / C330 | S130 file:mouse/Aldh7a1/Aldh7a1-uniprot.txt FT ACT_SITE 330 FT /note="Nucleophile" |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | ISO GO_REF:0000119 | ACCEPT | Summary: Broad NAD+-dependent aldehyde dehydrogenase activity on non-lysine aldehydes, including lipid-peroxidation-derived and medium-chain aldehydes. Reason: Purified human ALDH7A1 oxidizes several aldehyde substrates (PMID:20207735). Mouse is the 1:1 ortholog with the active site conserved. No experiment in mouse tests this directly. The inference rests on orthology to human ALDH7A1 (88.3% identity, conserved catalytic Glu296/Cys330, shared PAINT node PTN000192435 despite the PANTHER SF1/SF5 split, which looks like a classification artifact). The PAINT node carries GO:0004029 one level up (PTN000192422, with human as seed), so the activity is inferred for the whole family. This is accepted as a core but inferred activity; mouse-specific kinetics are lacking. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md human P49419 | 0.883 (539 columns) | E296 / C330 | S130 file:mouse/Aldh7a1/Aldh7a1-uniprot.txt FT ACT_SITE 330 FT /note="Nucleophile" |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | ISS GO_REF:0000024 | ACCEPT | Summary: Broad NAD+-dependent aldehyde dehydrogenase activity on non-lysine aldehydes, including lipid-peroxidation-derived and medium-chain aldehydes. Reason: Purified human ALDH7A1 oxidizes several aldehyde substrates (PMID:20207735). Mouse is the 1:1 ortholog with the active site conserved. No experiment in mouse tests this directly. The inference rests on orthology to human ALDH7A1 (88.3% identity, conserved catalytic Glu296/Cys330, shared PAINT node PTN000192435 despite the PANTHER SF1/SF5 split, which looks like a classification artifact). The PAINT node carries GO:0004029 one level up (PTN000192422, with human as seed), so the activity is inferred for the whole family. This is accepted as a core but inferred activity; mouse-specific kinetics are lacking. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md human P49419 | 0.883 (539 columns) | E296 / C330 | S130 file:mouse/Aldh7a1/Aldh7a1-uniprot.txt FT ACT_SITE 330 FT /note="Nucleophile" |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | ISS GO_REF:0000024 | ACCEPT | Summary: Broad NAD+-dependent aldehyde dehydrogenase activity on non-lysine aldehydes, including lipid-peroxidation-derived and medium-chain aldehydes. Reason: Purified human ALDH7A1 oxidizes several aldehyde substrates (PMID:20207735). Mouse is the 1:1 ortholog with the active site conserved. No experiment in mouse tests this directly. The inference rests on orthology to human ALDH7A1 (88.3% identity, conserved catalytic Glu296/Cys330, shared PAINT node PTN000192435 despite the PANTHER SF1/SF5 split, which looks like a classification artifact). The PAINT node carries GO:0004029 one level up (PTN000192422, with human as seed), so the activity is inferred for the whole family. This is accepted as a core but inferred activity; mouse-specific kinetics are lacking. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md human P49419 | 0.883 (539 columns) | E296 / C330 | S130 file:mouse/Aldh7a1/Aldh7a1-uniprot.txt FT ACT_SITE 330 FT /note="Nucleophile" |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | IEA GO_REF:0000120 | ACCEPT | Summary: L-aminoadipate-semialdehyde (AASA/P6C) dehydrogenase is the defining catalytic activity of ALDH7A1/antiquitin, and mouse genetic evidence supports it. Reason: In Aldh7a1-KO mice, P6C, alpha-AASA and pipecolate (the substrate and the metabolites upstream of it) accumulate in brain and liver, which is direct in vivo genetic evidence in this species that the enzyme performs the AASA oxidation step (PMID:32969477; confirmed in PMID:39661514). Purified-enzyme kinetics come from the human ortholog (Km 169 uM for AASA, PMID:20207735), which sits in the same PAINT clade. MGI:108186 is itself a seed for the GO:0004043 IBD at PTN000192435. This is the core activity, and all rows for this term are accepted. Supporting Evidence: PMID:32969477 three upstream lysine catabolic products (P6C, Ξ±-AASA and PIP) accumulated in significantly higher concentrations in brain and liver tissues of KO mice compared with low or undetectable levels in HET and WT mice PMID:32969477 we quantified multiple metabolic intermediates surrounding the ALDH7A1-catalyzed step in the lysine catabolism pathway in brain and liver tissues of heterozygous and homozygous KO mice versus their WT counterparts PMID:20207735 The recombinant human protein had a calculated K m of 169 ΞΌ m for AASA file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md The PAINT node PTN000192435 contains both mouse and human and carries the IBDs for GO:0004043 and GO:0019477 |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | IMP PMID:32969477 A novel mouse model for pyridoxine-dependent epilepsy due to... | ACCEPT | Summary: L-aminoadipate-semialdehyde (AASA/P6C) dehydrogenase is the defining catalytic activity of ALDH7A1/antiquitin, and mouse genetic evidence supports it. Reason: In Aldh7a1-KO mice, P6C, alpha-AASA and pipecolate (the substrate and the metabolites upstream of it) accumulate in brain and liver, which is direct in vivo genetic evidence in this species that the enzyme performs the AASA oxidation step (PMID:32969477; confirmed in PMID:39661514). Purified-enzyme kinetics come from the human ortholog (Km 169 uM for AASA, PMID:20207735), which sits in the same PAINT clade. MGI:108186 is itself a seed for the GO:0004043 IBD at PTN000192435. This is the core activity, and all rows for this term are accepted. Supporting Evidence: PMID:32969477 three upstream lysine catabolic products (P6C, Ξ±-AASA and PIP) accumulated in significantly higher concentrations in brain and liver tissues of KO mice compared with low or undetectable levels in HET and WT mice PMID:32969477 we quantified multiple metabolic intermediates surrounding the ALDH7A1-catalyzed step in the lysine catabolism pathway in brain and liver tissues of heterozygous and homozygous KO mice versus their WT counterparts PMID:20207735 The recombinant human protein had a calculated K m of 169 ΞΌ m for AASA file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md The PAINT node PTN000192435 contains both mouse and human and carries the IBDs for GO:0004043 and GO:0019477 |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | ISO GO_REF:0000119 | ACCEPT | Summary: L-aminoadipate-semialdehyde (AASA/P6C) dehydrogenase is the defining catalytic activity of ALDH7A1/antiquitin, and mouse genetic evidence supports it. Reason: In Aldh7a1-KO mice, P6C, alpha-AASA and pipecolate (the substrate and the metabolites upstream of it) accumulate in brain and liver, which is direct in vivo genetic evidence in this species that the enzyme performs the AASA oxidation step (PMID:32969477; confirmed in PMID:39661514). Purified-enzyme kinetics come from the human ortholog (Km 169 uM for AASA, PMID:20207735), which sits in the same PAINT clade. MGI:108186 is itself a seed for the GO:0004043 IBD at PTN000192435. This is the core activity, and all rows for this term are accepted. Supporting Evidence: PMID:32969477 three upstream lysine catabolic products (P6C, Ξ±-AASA and PIP) accumulated in significantly higher concentrations in brain and liver tissues of KO mice compared with low or undetectable levels in HET and WT mice PMID:32969477 we quantified multiple metabolic intermediates surrounding the ALDH7A1-catalyzed step in the lysine catabolism pathway in brain and liver tissues of heterozygous and homozygous KO mice versus their WT counterparts PMID:20207735 The recombinant human protein had a calculated K m of 169 ΞΌ m for AASA file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md The PAINT node PTN000192435 contains both mouse and human and carries the IBDs for GO:0004043 and GO:0019477 |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | ISS GO_REF:0000024 | ACCEPT | Summary: L-aminoadipate-semialdehyde (AASA/P6C) dehydrogenase is the defining catalytic activity of ALDH7A1/antiquitin, and mouse genetic evidence supports it. Reason: In Aldh7a1-KO mice, P6C, alpha-AASA and pipecolate (the substrate and the metabolites upstream of it) accumulate in brain and liver, which is direct in vivo genetic evidence in this species that the enzyme performs the AASA oxidation step (PMID:32969477; confirmed in PMID:39661514). Purified-enzyme kinetics come from the human ortholog (Km 169 uM for AASA, PMID:20207735), which sits in the same PAINT clade. MGI:108186 is itself a seed for the GO:0004043 IBD at PTN000192435. This is the core activity, and all rows for this term are accepted. Supporting Evidence: PMID:32969477 three upstream lysine catabolic products (P6C, Ξ±-AASA and PIP) accumulated in significantly higher concentrations in brain and liver tissues of KO mice compared with low or undetectable levels in HET and WT mice PMID:32969477 we quantified multiple metabolic intermediates surrounding the ALDH7A1-catalyzed step in the lysine catabolism pathway in brain and liver tissues of heterozygous and homozygous KO mice versus their WT counterparts PMID:20207735 The recombinant human protein had a calculated K m of 169 ΞΌ m for AASA file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md The PAINT node PTN000192435 contains both mouse and human and carries the IBDs for GO:0004043 and GO:0019477 |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nucleus. Reason: There is mouse evidence. Fractionation of mouse liver/kidney gave a nuclear pool, and immunohistochemistry showed nuclear staining in mouse cardiomyocytes and endothelial cells (PMID:20207735). No nuclear function is known, so the location is retained as non-core. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol PMID:20207735 In the heart, ALDH7A1 staining was observed in the cytosol and nuclei of cardiomyocytes as well as the nuclei of cardiac endothelial cells |
| GO:0005634 nucleus | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Nucleus. Reason: There is mouse evidence. Fractionation of mouse liver/kidney gave a nuclear pool, and immunohistochemistry showed nuclear staining in mouse cardiomyocytes and endothelial cells (PMID:20207735). No nuclear function is known, so the location is retained as non-core. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol PMID:20207735 In the heart, ALDH7A1 staining was observed in the cytosol and nuclei of cardiomyocytes as well as the nuclei of cardiac endothelial cells |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Nucleus. Reason: There is mouse evidence. Fractionation of mouse liver/kidney gave a nuclear pool, and immunohistochemistry showed nuclear staining in mouse cardiomyocytes and endothelial cells (PMID:20207735). No nuclear function is known, so the location is retained as non-core. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol PMID:20207735 In the heart, ALDH7A1 staining was observed in the cytosol and nuclei of cardiomyocytes as well as the nuclei of cardiac endothelial cells |
| GO:0005739 mitochondrion | HDA PMID:14651853 Integrated analysis of protein composition, tissue diversity... | ACCEPT | Summary: Mitochondrion. Isoform 1 (mALDH7A1_v2) carries an N-terminal mitochondrial presequence, and the protein is detected in mitochondria isolated from mouse tissues. Reason: There is direct mouse evidence. Fractionation of mouse liver and kidney found ALDH7A1 in mitochondrial fractions (PMID:20207735), and two proteomic surveys of mitochondria from mouse tissues detected it (PMID:14651853, PMID:18614015). Mouse transcript analysis identified a mitochondrial-presequence isoform. The AASA step of lysine degradation via saccharopine sits with the mitochondrial pathway. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol PMID:20207735 mALDH7A1_v2 utilizes an alternate upstream start codon, resulting in the addition of a mitochondrial signal sequence to the amino terminus of the protein. PMID:14651853 mitochondria from mouse brain, heart, kidney, and liver and combined the results PMID:18614015 machine learning to create a mitochondrial compendium of 1098 genes file:mouse/Aldh7a1/Aldh7a1-uniprot.txt FT TRANSIT 1..26 FT /note="Mitochondrion" |
| GO:0005739 mitochondrion | HDA PMID:18614015 A mitochondrial protein compendium elucidates complex I dise... | ACCEPT | Summary: Mitochondrion. Isoform 1 (mALDH7A1_v2) carries an N-terminal mitochondrial presequence, and the protein is detected in mitochondria isolated from mouse tissues. Reason: There is direct mouse evidence. Fractionation of mouse liver and kidney found ALDH7A1 in mitochondrial fractions (PMID:20207735), and two proteomic surveys of mitochondria from mouse tissues detected it (PMID:14651853, PMID:18614015). Mouse transcript analysis identified a mitochondrial-presequence isoform. The AASA step of lysine degradation via saccharopine sits with the mitochondrial pathway. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol PMID:20207735 mALDH7A1_v2 utilizes an alternate upstream start codon, resulting in the addition of a mitochondrial signal sequence to the amino terminus of the protein. PMID:14651853 mitochondria from mouse brain, heart, kidney, and liver and combined the results PMID:18614015 machine learning to create a mitochondrial compendium of 1098 genes file:mouse/Aldh7a1/Aldh7a1-uniprot.txt FT TRANSIT 1..26 FT /note="Mitochondrion" |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrion. Isoform 1 (mALDH7A1_v2) carries an N-terminal mitochondrial presequence, and the protein is detected in mitochondria isolated from mouse tissues. Reason: There is direct mouse evidence. Fractionation of mouse liver and kidney found ALDH7A1 in mitochondrial fractions (PMID:20207735), and two proteomic surveys of mitochondria from mouse tissues detected it (PMID:14651853, PMID:18614015). Mouse transcript analysis identified a mitochondrial-presequence isoform. The AASA step of lysine degradation via saccharopine sits with the mitochondrial pathway. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol PMID:20207735 mALDH7A1_v2 utilizes an alternate upstream start codon, resulting in the addition of a mitochondrial signal sequence to the amino terminus of the protein. PMID:14651853 mitochondria from mouse brain, heart, kidney, and liver and combined the results PMID:18614015 machine learning to create a mitochondrial compendium of 1098 genes file:mouse/Aldh7a1/Aldh7a1-uniprot.txt FT TRANSIT 1..26 FT /note="Mitochondrion" |
| GO:0005739 mitochondrion | ISO GO_REF:0000119 | ACCEPT | Summary: Mitochondrion. Isoform 1 (mALDH7A1_v2) carries an N-terminal mitochondrial presequence, and the protein is detected in mitochondria isolated from mouse tissues. Reason: There is direct mouse evidence. Fractionation of mouse liver and kidney found ALDH7A1 in mitochondrial fractions (PMID:20207735), and two proteomic surveys of mitochondria from mouse tissues detected it (PMID:14651853, PMID:18614015). Mouse transcript analysis identified a mitochondrial-presequence isoform. The AASA step of lysine degradation via saccharopine sits with the mitochondrial pathway. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol PMID:20207735 mALDH7A1_v2 utilizes an alternate upstream start codon, resulting in the addition of a mitochondrial signal sequence to the amino terminus of the protein. PMID:14651853 mitochondria from mouse brain, heart, kidney, and liver and combined the results PMID:18614015 machine learning to create a mitochondrial compendium of 1098 genes file:mouse/Aldh7a1/Aldh7a1-uniprot.txt FT TRANSIT 1..26 FT /note="Mitochondrion" |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrion. Isoform 1 (mALDH7A1_v2) carries an N-terminal mitochondrial presequence, and the protein is detected in mitochondria isolated from mouse tissues. Reason: There is direct mouse evidence. Fractionation of mouse liver and kidney found ALDH7A1 in mitochondrial fractions (PMID:20207735), and two proteomic surveys of mitochondria from mouse tissues detected it (PMID:14651853, PMID:18614015). Mouse transcript analysis identified a mitochondrial-presequence isoform. The AASA step of lysine degradation via saccharopine sits with the mitochondrial pathway. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol PMID:20207735 mALDH7A1_v2 utilizes an alternate upstream start codon, resulting in the addition of a mitochondrial signal sequence to the amino terminus of the protein. PMID:14651853 mitochondria from mouse brain, heart, kidney, and liver and combined the results PMID:18614015 machine learning to create a mitochondrial compendium of 1098 genes file:mouse/Aldh7a1/Aldh7a1-uniprot.txt FT TRANSIT 1..26 FT /note="Mitochondrion" |
| GO:0005759 mitochondrial matrix | IDA PMID:20207735 Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme invol... | ACCEPT | Summary: Mitochondrial matrix. Reason: PMID:20207735 shows mouse ALDH7A1 in purified mitochondrial fractions, and the mitochondrial isoform has a cleavable presequence and is a soluble enzyme. The cached text does not show a sub-mitochondrial fractionation, but matrix is the expected compartment for a soluble presequence-imported ALDH acting in lysine degradation. I defer to the MGI curator's IDA. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol file:mouse/Aldh7a1/Aldh7a1-uniprot.txt FT TRANSIT 1..26 FT /note="Mitochondrion" |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Cytosol. The non-mitochondrial isoform (isoform 2, mALDH7A1_v1) lacks the presequence, and the protein is detected in mouse cytosolic fractions. Reason: Mouse liver/kidney fractionation found ALDH7A1 in cytosolic fractions, and immunohistochemistry of mouse heart, liver and kidney showed cytosolic staining (PMID:20207735). This is direct mouse evidence for the IEA/ISO/ISS rows. The PAINT node also carries a cytosol IBD. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol PMID:20207735 In the heart, ALDH7A1 staining was observed in the cytosol and nuclei of cardiomyocytes as well as the nuclei of cardiac endothelial cells file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0005829 cytosol | ISO GO_REF:0000119 | ACCEPT | Summary: Cytosol. The non-mitochondrial isoform (isoform 2, mALDH7A1_v1) lacks the presequence, and the protein is detected in mouse cytosolic fractions. Reason: Mouse liver/kidney fractionation found ALDH7A1 in cytosolic fractions, and immunohistochemistry of mouse heart, liver and kidney showed cytosolic staining (PMID:20207735). This is direct mouse evidence for the IEA/ISO/ISS rows. The PAINT node also carries a cytosol IBD. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol PMID:20207735 In the heart, ALDH7A1 staining was observed in the cytosol and nuclei of cardiomyocytes as well as the nuclei of cardiac endothelial cells file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: Cytosol. The non-mitochondrial isoform (isoform 2, mALDH7A1_v1) lacks the presequence, and the protein is detected in mouse cytosolic fractions. Reason: Mouse liver/kidney fractionation found ALDH7A1 in cytosolic fractions, and immunohistochemistry of mouse heart, liver and kidney showed cytosolic staining (PMID:20207735). This is direct mouse evidence for the IEA/ISO/ISS rows. The PAINT node also carries a cytosol IBD. Supporting Evidence: PMID:20207735 Subcellular fractionation of liver and kidney revealed ALDH7A1 localization in nuclei, mitochondria, and cytosol PMID:20207735 In the heart, ALDH7A1 staining was observed in the cytosol and nuclei of cardiomyocytes as well as the nuclei of cardiac endothelial cells file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Plasma membrane (stress-recruited pool, inferred from human). Reason: In human cells, the non-mitochondrial ALDH7A1 isoform is recruited to Golgi and other membranes, where it generates NADH; AMPK phosphorylation at Ser130 (Ser102 in isoform-2 numbering) promotes this (PMID:31492851, PMID:40233740). PAINT propagated this location to PTN000192435, which includes mouse. However, no mouse experiment shows the membrane pool, and mouse fractionation found no microsomal ALDH7A1 (PMID:20207735). In addition, the AMPK site is Arg130 in mouse and rat. Membrane association may still occur by other means, so the location is kept as a non-core inference and should not be used as an experimentally established mouse fact. Supporting Evidence: PMID:40233740 ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0005886 plasma membrane | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Plasma membrane (stress-recruited pool, inferred from human). Reason: In human cells, the non-mitochondrial ALDH7A1 isoform is recruited to Golgi and other membranes, where it generates NADH; AMPK phosphorylation at Ser130 (Ser102 in isoform-2 numbering) promotes this (PMID:31492851, PMID:40233740). PAINT propagated this location to PTN000192435, which includes mouse. However, no mouse experiment shows the membrane pool, and mouse fractionation found no microsomal ALDH7A1 (PMID:20207735). In addition, the AMPK site is Arg130 in mouse and rat. Membrane association may still occur by other means, so the location is kept as a non-core inference and should not be used as an experimentally established mouse fact. Supporting Evidence: PMID:40233740 ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0005886 plasma membrane | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Plasma membrane (stress-recruited pool, inferred from human). Reason: In human cells, the non-mitochondrial ALDH7A1 isoform is recruited to Golgi and other membranes, where it generates NADH; AMPK phosphorylation at Ser130 (Ser102 in isoform-2 numbering) promotes this (PMID:31492851, PMID:40233740). PAINT propagated this location to PTN000192435, which includes mouse. However, no mouse experiment shows the membrane pool, and mouse fractionation found no microsomal ALDH7A1 (PMID:20207735). In addition, the AMPK site is Arg130 in mouse and rat. Membrane association may still occur by other means, so the location is kept as a non-core inference and should not be used as an experimentally established mouse fact. Supporting Evidence: PMID:40233740 ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Plasma membrane (stress-recruited pool, inferred from human). Reason: In human cells, the non-mitochondrial ALDH7A1 isoform is recruited to Golgi and other membranes, where it generates NADH; AMPK phosphorylation at Ser130 (Ser102 in isoform-2 numbering) promotes this (PMID:31492851, PMID:40233740). PAINT propagated this location to PTN000192435, which includes mouse. However, no mouse experiment shows the membrane pool, and mouse fractionation found no microsomal ALDH7A1 (PMID:20207735). In addition, the AMPK site is Arg130 in mouse and rat. Membrane association may still occur by other means, so the location is kept as a non-core inference and should not be used as an experimentally established mouse fact. Supporting Evidence: PMID:40233740 ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Plasma membrane (stress-recruited pool, inferred from human). Reason: In human cells, the non-mitochondrial ALDH7A1 isoform is recruited to Golgi and other membranes, where it generates NADH; AMPK phosphorylation at Ser130 (Ser102 in isoform-2 numbering) promotes this (PMID:31492851, PMID:40233740). PAINT propagated this location to PTN000192435, which includes mouse. However, no mouse experiment shows the membrane pool, and mouse fractionation found no microsomal ALDH7A1 (PMID:20207735). In addition, the AMPK site is Arg130 in mouse and rat. Membrane association may still occur by other means, so the location is kept as a non-core inference and should not be used as an experimentally established mouse fact. Supporting Evidence: PMID:40233740 ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0006895 Golgi to endosome transport | ISO GO_REF:0000119 | REMOVE | Summary: Membrane transport process transferred by ISO from human. Reason: ALDH7A1 does not carry out membrane trafficking. In human cells it inhibits COPI fission and several transport pathways during energy stress, because the NADH it makes acts on BARS (PMID:31492851). An 'involved in transport' annotation therefore misstates the human finding (at most, the role is negative regulation). For mouse there is also no experiment, the AMPK regulatory site is not conserved (R130), and PAINT did not propagate any transport term to PTN000192435. Propagation Review Root cause: SOURCE BAD Failure modes: REGULATORY SIGN INVERSION ROLE CONFLATION Sources checked: UniProtKB:P49419 Β· ALDH7A1 SOURCE BAD human ALDH7A1 inhibits these transport pathways (PMID:31492851) and is not a transport participant Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md No IBD at this node covers ferroptosis, energy homeostasis or the membrane-transport regulation terms. |
| GO:0008333 endosome to lysosome transport | ISO GO_REF:0000119 | REMOVE | Summary: Membrane transport process transferred by ISO from human. Reason: ALDH7A1 does not carry out membrane trafficking. In human cells it inhibits COPI fission and several transport pathways during energy stress, because the NADH it makes acts on BARS (PMID:31492851). An 'involved in transport' annotation therefore misstates the human finding (at most, the role is negative regulation). For mouse there is also no experiment, the AMPK regulatory site is not conserved (R130), and PAINT did not propagate any transport term to PTN000192435. Propagation Review Root cause: SOURCE BAD Failure modes: REGULATORY SIGN INVERSION ROLE CONFLATION Sources checked: UniProtKB:P49419 Β· ALDH7A1 SOURCE BAD human ALDH7A1 inhibits these transport pathways (PMID:31492851) and is not a transport participant Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md No IBD at this node covers ferroptosis, energy homeostasis or the membrane-transport regulation terms. |
| GO:0008802 betaine-aldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Betaine aldehyde oxidation to glycine betaine. Reason: Human recombinant ALDH7A1 oxidizes betaine aldehyde and protects against hyperosmotic stress when expressed in CHO cells (PMID:20207735). PAINT placed a GO:0008802 IBD at PTN000192435, which includes mouse. The dedicated betaine aldehyde dehydrogenase in mammals is ALDH9A1, and no mouse experiment tests this activity, so I keep it as a real but secondary, inferred activity. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0008802 betaine-aldehyde dehydrogenase (NAD+) activity | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Betaine aldehyde oxidation to glycine betaine. Reason: Human recombinant ALDH7A1 oxidizes betaine aldehyde and protects against hyperosmotic stress when expressed in CHO cells (PMID:20207735). PAINT placed a GO:0008802 IBD at PTN000192435, which includes mouse. The dedicated betaine aldehyde dehydrogenase in mammals is ALDH9A1, and no mouse experiment tests this activity, so I keep it as a real but secondary, inferred activity. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0008802 betaine-aldehyde dehydrogenase (NAD+) activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Betaine aldehyde oxidation to glycine betaine. Reason: Human recombinant ALDH7A1 oxidizes betaine aldehyde and protects against hyperosmotic stress when expressed in CHO cells (PMID:20207735). PAINT placed a GO:0008802 IBD at PTN000192435, which includes mouse. The dedicated betaine aldehyde dehydrogenase in mammals is ALDH9A1, and no mouse experiment tests this activity, so I keep it as a real but secondary, inferred activity. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md It also carries IBDs for GO:0008802 and for the locations mitochondrion, cytosol, nucleus, Golgi membrane and plasma membrane. |
| GO:0009063 amino acid catabolic process | IMP PMID:32969477 A novel mouse model for pyridoxine-dependent epilepsy due to... | MODIFY | Summary: Amino acid catabolic process, from the mouse KO studies. Reason: The evidence is correct but the term is too general. Both papers specifically show a block in lysine catabolism, so GO:0019477 L-lysine catabolic process (a descendant of GO:0009063, already carried by this gene) is the right term. The broader amino-acid changes reported in KO brain are downstream effects and do not show ALDH7A1 participating in other amino acid catabolic pathways. Proposed replacements: L-lysine catabolic process Supporting Evidence: PMID:32969477 three upstream lysine catabolic products (P6C, Ξ±-AASA and PIP) accumulated in significantly higher concentrations in brain and liver tissues of KO mice compared with low or undetectable levels in HET and WT mice PMID:39661514 of tissues from Aldh7a1-deficient mice, which reveal tissue-specific differences |
| GO:0009063 amino acid catabolic process | IMP PMID:39661514 Restricting lysine normalizes toxic catabolites associated w... | MODIFY | Summary: Amino acid catabolic process, from the mouse KO studies. Reason: The evidence is correct but the term is too general. Both papers specifically show a block in lysine catabolism, so GO:0019477 L-lysine catabolic process (a descendant of GO:0009063, already carried by this gene) is the right term. The broader amino-acid changes reported in KO brain are downstream effects and do not show ALDH7A1 participating in other amino acid catabolic pathways. Proposed replacements: L-lysine catabolic process Supporting Evidence: PMID:32969477 three upstream lysine catabolic products (P6C, Ξ±-AASA and PIP) accumulated in significantly higher concentrations in brain and liver tissues of KO mice compared with low or undetectable levels in HET and WT mice PMID:39661514 of tissues from Aldh7a1-deficient mice, which reveal tissue-specific differences |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic oxidoreductase activity from InterPro aldehyde dehydrogenase domain mappings. Reason: Correct but far too general. The protein belongs to the aldehyde dehydrogenase family and has a conserved Glu/Cys catalytic pair. The specific activities supported elsewhere in this review are GO:0004043 (mouse IMP) and GO:0004029. Proposed replacements: L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity aldehyde dehydrogenase (NAD+) activity Supporting Evidence: file:mouse/Aldh7a1/Aldh7a1-uniprot.txt Belongs to the aldehyde dehydrogenase family. file:mouse/Aldh7a1/Aldh7a1-uniprot.txt FT ACT_SITE 330 FT /note="Nucleophile" |
| GO:0016655 oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor | ISO GO_REF:0000119 | REMOVE | Summary: Quinone oxidoreductase activity (NAD(P)H as donor), transferred by ISO from human. Reason: This activity belongs to FSP1/AIFM2, not ALDH7A1. In the ferroptosis mechanism of PMID:40233740, ALDH7A1 oxidizes aldehydes and generates membrane NADH, and FSP1 then uses that NADH to reduce quinones. ALDH7A1 uses NAD+ as acceptor and an aldehyde as donor, so it is not an NAD(P)H:quinone oxidoreductase. The human review records the same problem in GO-CAM 680ad14200003459. The ISO transfer therefore spreads a mis-assigned activity, and it is removed for mouse. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P49419 Β· ALDH7A1 SOURCE BAD human ALDH7A1 supplies NADH; the quinone reduction is FSP1's activity (PMID:40233740) Supporting Evidence: PMID:40233740 Ferroptosis suppressor protein 1 (FSP1) protects against this death by PMID:40233740 ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming |
| GO:0019477 L-lysine catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: L-lysine catabolism via the saccharopine/pipecolate routes. ALDH7A1 catalyzes the AASA/P6C to alpha-aminoadipate step. Reason: There is direct mouse genetic evidence. Aldh7a1-KO mice accumulate the lysine catabolites upstream of the ALDH7A1 step in brain and liver, and they develop seizures on a high-lysine diet (PMID:32969477, PMID:39661514). The enzyme carries out a catalytic step of the pathway, so this is participation and not only necessity. The term is also supported by the GO:0019477 IBD at PTN000192435, for which mouse is a seed. This is the core process. Supporting Evidence: PMID:32969477 three upstream lysine catabolic products (P6C, Ξ±-AASA and PIP) accumulated in significantly higher concentrations in brain and liver tissues of KO mice compared with low or undetectable levels in HET and WT mice PMID:39661514 of tissues from Aldh7a1-deficient mice, which reveal tissue-specific differences file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md The PAINT node PTN000192435 contains both mouse and human and carries the IBDs for GO:0004043 and GO:0019477 |
| GO:0019477 L-lysine catabolic process | IMP PMID:32969477 A novel mouse model for pyridoxine-dependent epilepsy due to... | ACCEPT | Summary: L-lysine catabolism via the saccharopine/pipecolate routes. ALDH7A1 catalyzes the AASA/P6C to alpha-aminoadipate step. Reason: There is direct mouse genetic evidence. Aldh7a1-KO mice accumulate the lysine catabolites upstream of the ALDH7A1 step in brain and liver, and they develop seizures on a high-lysine diet (PMID:32969477, PMID:39661514). The enzyme carries out a catalytic step of the pathway, so this is participation and not only necessity. The term is also supported by the GO:0019477 IBD at PTN000192435, for which mouse is a seed. This is the core process. Supporting Evidence: PMID:32969477 three upstream lysine catabolic products (P6C, Ξ±-AASA and PIP) accumulated in significantly higher concentrations in brain and liver tissues of KO mice compared with low or undetectable levels in HET and WT mice PMID:39661514 of tissues from Aldh7a1-deficient mice, which reveal tissue-specific differences file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md The PAINT node PTN000192435 contains both mouse and human and carries the IBDs for GO:0004043 and GO:0019477 |
| GO:0019477 L-lysine catabolic process | IMP PMID:32969477 A novel mouse model for pyridoxine-dependent epilepsy due to... | ACCEPT | Summary: L-lysine catabolism via the saccharopine/pipecolate routes. ALDH7A1 catalyzes the AASA/P6C to alpha-aminoadipate step. Reason: There is direct mouse genetic evidence. Aldh7a1-KO mice accumulate the lysine catabolites upstream of the ALDH7A1 step in brain and liver, and they develop seizures on a high-lysine diet (PMID:32969477, PMID:39661514). The enzyme carries out a catalytic step of the pathway, so this is participation and not only necessity. The term is also supported by the GO:0019477 IBD at PTN000192435, for which mouse is a seed. This is the core process. Supporting Evidence: PMID:32969477 three upstream lysine catabolic products (P6C, Ξ±-AASA and PIP) accumulated in significantly higher concentrations in brain and liver tissues of KO mice compared with low or undetectable levels in HET and WT mice PMID:39661514 of tissues from Aldh7a1-deficient mice, which reveal tissue-specific differences file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md The PAINT node PTN000192435 contains both mouse and human and carries the IBDs for GO:0004043 and GO:0019477 |
| GO:0019477 L-lysine catabolic process | IMP PMID:39661514 Restricting lysine normalizes toxic catabolites associated w... | ACCEPT | Summary: L-lysine catabolism via the saccharopine/pipecolate routes. ALDH7A1 catalyzes the AASA/P6C to alpha-aminoadipate step. Reason: There is direct mouse genetic evidence. Aldh7a1-KO mice accumulate the lysine catabolites upstream of the ALDH7A1 step in brain and liver, and they develop seizures on a high-lysine diet (PMID:32969477, PMID:39661514). The enzyme carries out a catalytic step of the pathway, so this is participation and not only necessity. The term is also supported by the GO:0019477 IBD at PTN000192435, for which mouse is a seed. This is the core process. Supporting Evidence: PMID:32969477 three upstream lysine catabolic products (P6C, Ξ±-AASA and PIP) accumulated in significantly higher concentrations in brain and liver tissues of KO mice compared with low or undetectable levels in HET and WT mice PMID:39661514 of tissues from Aldh7a1-deficient mice, which reveal tissue-specific differences file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md The PAINT node PTN000192435 contains both mouse and human and carries the IBDs for GO:0004043 and GO:0019477 |
| GO:0019477 L-lysine catabolic process | ISO GO_REF:0000119 | ACCEPT | Summary: L-lysine catabolism via the saccharopine/pipecolate routes. ALDH7A1 catalyzes the AASA/P6C to alpha-aminoadipate step. Reason: There is direct mouse genetic evidence. Aldh7a1-KO mice accumulate the lysine catabolites upstream of the ALDH7A1 step in brain and liver, and they develop seizures on a high-lysine diet (PMID:32969477, PMID:39661514). The enzyme carries out a catalytic step of the pathway, so this is participation and not only necessity. The term is also supported by the GO:0019477 IBD at PTN000192435, for which mouse is a seed. This is the core process. Supporting Evidence: PMID:32969477 three upstream lysine catabolic products (P6C, Ξ±-AASA and PIP) accumulated in significantly higher concentrations in brain and liver tissues of KO mice compared with low or undetectable levels in HET and WT mice PMID:39661514 of tissues from Aldh7a1-deficient mice, which reveal tissue-specific differences file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md The PAINT node PTN000192435 contains both mouse and human and carries the IBDs for GO:0004043 and GO:0019477 |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Homo-oligomerization (homotetramer). Reason: The ALDH7A1 enzyme is a homotetramer, shown for the human protein (UniProt SUBUNIT by similarity to P49419). Self-association is needed for the catalytic assembly but is a structural property and not the protein's functional output, so I keep it as non-core. It is inferred for mouse. Supporting Evidence: file:mouse/Aldh7a1/Aldh7a1-uniprot.txt Homotetramer. {ECO:0000250|UniProtKB:P49419}. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md human P49419 | 0.883 (539 columns) | E296 / C330 | S130 |
| GO:0042802 identical protein binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Homo-oligomerization (homotetramer). Reason: The ALDH7A1 enzyme is a homotetramer, shown for the human protein (UniProt SUBUNIT by similarity to P49419). Self-association is needed for the catalytic assembly but is a structural property and not the protein's functional output, so I keep it as non-core. It is inferred for mouse. Supporting Evidence: file:mouse/Aldh7a1/Aldh7a1-uniprot.txt Homotetramer. {ECO:0000250|UniProtKB:P49419}. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md human P49419 | 0.883 (539 columns) | E296 / C330 | S130 |
| GO:0042802 identical protein binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Homo-oligomerization (homotetramer). Reason: The ALDH7A1 enzyme is a homotetramer, shown for the human protein (UniProt SUBUNIT by similarity to P49419). Self-association is needed for the catalytic assembly but is a structural property and not the protein's functional output, so I keep it as non-core. It is inferred for mouse. Supporting Evidence: file:mouse/Aldh7a1/Aldh7a1-uniprot.txt Homotetramer. {ECO:0000250|UniProtKB:P49419}. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md human P49419 | 0.883 (539 columns) | E296 / C330 | S130 |
| GO:0042997 negative regulation of Golgi to plasma membrane protein transport | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Negative regulation of Golgi to plasma membrane protein transport (human COPI/BARS finding). Reason: This process was shown in human HeLa/other human cells (PMID:31492851 for transport and energy homeostasis; PMID:40233740 for ferroptosis). It depends on stress-triggered membrane recruitment of ALDH7A1, which AMPK phosphorylation of Ser130 promotes. In mouse that residue is Arg130, there are no mouse experiments, and PAINT curators did not propagate these process terms to the vertebrate ALDH7A1 node PTN000192435 even though they propagated its activities and locations. I treat that omission as deliberate. The underlying NADH-generating and aldehyde-consuming chemistry is conserved, so the process is not implausible, but for mouse it is an over-annotation until it is tested. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P49419-2 Β· ALDH7A1 SUPPORTS SOURCE BUT NOT TARGET human evidence depends on AMPK-site Ser130 recruitment; mouse has Arg130 and no mouse data; not propagated by PAINT Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md No IBD at this node covers ferroptosis, energy homeostasis or the membrane-transport regulation terms. |
| GO:0042997 negative regulation of Golgi to plasma membrane protein transport | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Negative regulation of Golgi to plasma membrane protein transport (human COPI/BARS finding). Reason: This process was shown in human HeLa/other human cells (PMID:31492851 for transport and energy homeostasis; PMID:40233740 for ferroptosis). It depends on stress-triggered membrane recruitment of ALDH7A1, which AMPK phosphorylation of Ser130 promotes. In mouse that residue is Arg130, there are no mouse experiments, and PAINT curators did not propagate these process terms to the vertebrate ALDH7A1 node PTN000192435 even though they propagated its activities and locations. I treat that omission as deliberate. The underlying NADH-generating and aldehyde-consuming chemistry is conserved, so the process is not implausible, but for mouse it is an over-annotation until it is tested. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P49419-2 Β· ALDH7A1 SUPPORTS SOURCE BUT NOT TARGET human evidence depends on AMPK-site Ser130 recruitment; mouse has Arg130 and no mouse data; not propagated by PAINT Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md No IBD at this node covers ferroptosis, energy homeostasis or the membrane-transport regulation terms. |
| GO:0048227 plasma membrane to endosome transport | ISO GO_REF:0000119 | REMOVE | Summary: Membrane transport process transferred by ISO from human. Reason: ALDH7A1 does not carry out membrane trafficking. In human cells it inhibits COPI fission and several transport pathways during energy stress, because the NADH it makes acts on BARS (PMID:31492851). An 'involved in transport' annotation therefore misstates the human finding (at most, the role is negative regulation). For mouse there is also no experiment, the AMPK regulatory site is not conserved (R130), and PAINT did not propagate any transport term to PTN000192435. Propagation Review Root cause: SOURCE BAD Failure modes: REGULATORY SIGN INVERSION ROLE CONFLATION Sources checked: UniProtKB:P49419 Β· ALDH7A1 SOURCE BAD human ALDH7A1 inhibits these transport pathways (PMID:31492851) and is not a transport participant Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md No IBD at this node covers ferroptosis, energy homeostasis or the membrane-transport regulation terms. |
| GO:0052814 medium-chain fatty aldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Oxidation of medium-chain fatty aldehydes such as hexanal, octanal and nonanal (Rhea mapping from curated UniProt reactions). Reason: The UniProt reactions behind this Rhea-based IEA are by similarity to human (ECO:0000250), where lipid-peroxidation aldehydes are good substrates (PMID:20207735). The term is consistent with the broad aldehyde dehydrogenase activity, but it is inferred and secondary to the AASA activity in mouse. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md human P49419 | 0.883 (539 columns) | E296 / C330 | S130 |
| GO:0097009 energy homeostasis | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Energy homeostasis (human hypoxia/starvation finding). Reason: This process was shown in human HeLa/other human cells (PMID:31492851 for transport and energy homeostasis; PMID:40233740 for ferroptosis). It depends on stress-triggered membrane recruitment of ALDH7A1, which AMPK phosphorylation of Ser130 promotes. In mouse that residue is Arg130, there are no mouse experiments, and PAINT curators did not propagate these process terms to the vertebrate ALDH7A1 node PTN000192435 even though they propagated its activities and locations. I treat that omission as deliberate. The underlying NADH-generating and aldehyde-consuming chemistry is conserved, so the process is not implausible, but for mouse it is an over-annotation until it is tested. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P49419-2 Β· ALDH7A1 SUPPORTS SOURCE BUT NOT TARGET human evidence depends on AMPK-site Ser130 recruitment; mouse has Arg130 and no mouse data; not propagated by PAINT Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md No IBD at this node covers ferroptosis, energy homeostasis or the membrane-transport regulation terms. |
| GO:0097009 energy homeostasis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Energy homeostasis (human hypoxia/starvation finding). Reason: This process was shown in human HeLa/other human cells (PMID:31492851 for transport and energy homeostasis; PMID:40233740 for ferroptosis). It depends on stress-triggered membrane recruitment of ALDH7A1, which AMPK phosphorylation of Ser130 promotes. In mouse that residue is Arg130, there are no mouse experiments, and PAINT curators did not propagate these process terms to the vertebrate ALDH7A1 node PTN000192435 even though they propagated its activities and locations. I treat that omission as deliberate. The underlying NADH-generating and aldehyde-consuming chemistry is conserved, so the process is not implausible, but for mouse it is an over-annotation until it is tested. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P49419-2 Β· ALDH7A1 SUPPORTS SOURCE BUT NOT TARGET human evidence depends on AMPK-site Ser130 recruitment; mouse has Arg130 and no mouse data; not propagated by PAINT Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md No IBD at this node covers ferroptosis, energy homeostasis or the membrane-transport regulation terms. |
| GO:0110076 negative regulation of ferroptosis | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Negative regulation of ferroptosis (human finding). Reason: This process was shown in human HeLa/other human cells (PMID:31492851 for transport and energy homeostasis; PMID:40233740 for ferroptosis). It depends on stress-triggered membrane recruitment of ALDH7A1, which AMPK phosphorylation of Ser130 promotes. In mouse that residue is Arg130, there are no mouse experiments, and PAINT curators did not propagate these process terms to the vertebrate ALDH7A1 node PTN000192435 even though they propagated its activities and locations. I treat that omission as deliberate. The underlying NADH-generating and aldehyde-consuming chemistry is conserved, so the process is not implausible, but for mouse it is an over-annotation until it is tested. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P49419-2 Β· ALDH7A1 SUPPORTS SOURCE BUT NOT TARGET human evidence depends on AMPK-site Ser130 recruitment; mouse has Arg130 and no mouse data; not propagated by PAINT Supporting Evidence: PMID:40233740 ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md No IBD at this node covers ferroptosis, energy homeostasis or the membrane-transport regulation terms. |
| GO:0110076 negative regulation of ferroptosis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Negative regulation of ferroptosis (human finding). Reason: This process was shown in human HeLa/other human cells (PMID:31492851 for transport and energy homeostasis; PMID:40233740 for ferroptosis). It depends on stress-triggered membrane recruitment of ALDH7A1, which AMPK phosphorylation of Ser130 promotes. In mouse that residue is Arg130, there are no mouse experiments, and PAINT curators did not propagate these process terms to the vertebrate ALDH7A1 node PTN000192435 even though they propagated its activities and locations. I treat that omission as deliberate. The underlying NADH-generating and aldehyde-consuming chemistry is conserved, so the process is not implausible, but for mouse it is an over-annotation until it is tested. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P49419-2 Β· ALDH7A1 SUPPORTS SOURCE BUT NOT TARGET human evidence depends on AMPK-site Ser130 recruitment; mouse has Arg130 and no mouse data; not propagated by PAINT Supporting Evidence: PMID:40233740 ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md No IBD at this node covers ferroptosis, energy homeostasis or the membrane-transport regulation terms. |
| GO:1905750 obsolete negative regulation of endosome to plasma membrane protein transport | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Negative regulation of endosome to plasma membrane protein transport (human finding). The GOA label marks the term obsolete; OLS still lists it as active. Reason: This process was shown in human HeLa/other human cells (PMID:31492851 for transport and energy homeostasis; PMID:40233740 for ferroptosis). It depends on stress-triggered membrane recruitment of ALDH7A1, which AMPK phosphorylation of Ser130 promotes. In mouse that residue is Arg130, there are no mouse experiments, and PAINT curators did not propagate these process terms to the vertebrate ALDH7A1 node PTN000192435 even though they propagated its activities and locations. I treat that omission as deliberate. The underlying NADH-generating and aldehyde-consuming chemistry is conserved, so the process is not implausible, but for mouse it is an over-annotation until it is tested. This judgment is independent of the term's obsoletion status. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P49419-2 Β· ALDH7A1 SUPPORTS SOURCE BUT NOT TARGET human evidence depends on AMPK-site Ser130 recruitment; mouse has Arg130 and no mouse data; not propagated by PAINT Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md No IBD at this node covers ferroptosis, energy homeostasis or the membrane-transport regulation terms. |
| GO:1905750 obsolete negative regulation of endosome to plasma membrane protein transport | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Negative regulation of endosome to plasma membrane protein transport (human finding). The GOA label marks the term obsolete; OLS still lists it as active. Reason: This process was shown in human HeLa/other human cells (PMID:31492851 for transport and energy homeostasis; PMID:40233740 for ferroptosis). It depends on stress-triggered membrane recruitment of ALDH7A1, which AMPK phosphorylation of Ser130 promotes. In mouse that residue is Arg130, there are no mouse experiments, and PAINT curators did not propagate these process terms to the vertebrate ALDH7A1 node PTN000192435 even though they propagated its activities and locations. I treat that omission as deliberate. The underlying NADH-generating and aldehyde-consuming chemistry is conserved, so the process is not implausible, but for mouse it is an over-annotation until it is tested. This judgment is independent of the term's obsoletion status. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P49419-2 Β· ALDH7A1 SUPPORTS SOURCE BUT NOT TARGET human evidence depends on AMPK-site Ser130 recruitment; mouse has Arg130 and no mouse data; not propagated by PAINT Supporting Evidence: PMID:31492851 Thus, we explored whether NADH generated by ALDH7A1 activity could target BARS in explaining how ALDH7A1 inhibits COPI vesicle fission. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md Mouse and rat carry Arg and Xenopus carries His at this position, so this AMPK site is not conserved in mouse. file:mouse/Aldh7a1/Aldh7a1-bioinformatics/RESULTS.md No IBD at this node covers ferroptosis, energy homeostasis or the membrane-transport regulation terms. |
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Download this section (compressed HTML)Q: Is mouse Aldh7a1 (Arg at the position of human AMPK site Ser130) recruited to Golgi/plasma membranes under energy or ferroptotic stress, and does it then restrain COPI transport or support FSP1 as human ALDH7A1 does?
Q: Is the PANTHER 19.0 placement of human P49419 in PTHR43521:SF5, apart from all other vertebrate orthologs in SF1, a classification artifact, and should it be reconciled?
Q: Should GO:0016655 be removed from the ALDH7A1 nodes of GO-CAM 680ad14200003459, given that FSP1, not ALDH7A1, reduces the quinone?
Experiment: Fractionate membranes from wild-type and Aldh7a1-KO mouse cells (e.g. MEFs or hepatocytes) under AICAR, hypoxia or RSL3 treatment and measure membrane NADH, COPI transport and ferroptosis sensitivity. Rescue with mouse Aldh7a1 versus an R130S variant to test whether gaining the human AMPK site confers stress-induced recruitment.
Experiment: Run steady-state kinetics of purified mouse Aldh7a1 (mitochondrial-mature and cytosolic forms) on AASA/P6C, betaine aldehyde, 4-HNE and hexanal to establish the mouse substrate range directly.
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