Aldh1l1

Summary: Aldh1l1 clearly supports NADP-dependent aldehyde oxidation, but exclusion of all NAD+-dependent activity remains unresolved.

Reason: The PAINT GO:0004029 assertion is at PTN000192666 and includes mouse Aldh1l1 among experimental descendants. NADP+ preference alone does not prove complete loss of NAD+ turnover, and the NADP-specific term is a different cofactor reaction rather than a more specific child of the NAD+ reaction. The available rat studies establish NADP-dependent chemistry. Leave this cofactor-specific assertion unresolved pending intact-enzyme NAD+/NADP+ comparisons and inspection of the ortholog evidence; do not diagnose paralog error from family breadth. The independent OpenScientist report recommends rejection, but its own limitations explicitly acknowledge the absence of NAD+ kinetics rather than a formal negative result. PMID:17302434 explains NADP preference through a phosphate contact; this also does not establish zero NAD+ turnover. Retain UNDECIDED after adjudication, pending a direct cofactor assay.

Summary: The mitochondrial ancestor is supported by ALDH1L2, whose added targeting presequence distinguishes it from rat cytosolic ALDH1L1.

Reason: The mitochondrial IBD at PTN008524390 in PTHR11699 is supported by human ALDH1L2 (Q3SY69). The independent report adds a concrete targeting comparison: rat ALDH1L1 begins MKIAVIGQSL and lacks the additional N-terminal segment present in ALDH1L2. This was checked against the P28037 sequence and the primary full-text paralog comparison in PMID:20498374, which characterizes an additional 22-residue ALDH1L2 leader and demonstrates mitochondrial localization of its fusion construct. PMID:21238436 independently describes this targeting distinction. The challenge is thus a paralog-specific targeting acquisition extending across the broad ancestor, not merely absence of a rat mitochondrial experiment or prevalence of cytosolic observations. A rare noncanonical secondary pool is not formally excluded, but the demonstrated targeting divergence supports removing this general mitochondrial inference.

Summary: aldehyde metabolic process is retained as contextual support for Aldh1l1, but it is not the core function (IBA, GO_REF:0000033).

Reason: aldehyde metabolic process is biologically related to Aldh1l1, but it is broader, downstream, or regulatory context relative to cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining NADPH regeneration as a direct annotation (IBA, GO_REF:0000033).

Reason: NADPH regeneration is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH. The acceptance rests on this independent enzymological support, not on the phylogenetic inference alone (see propagation note on the current PAINT slice).

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IBA, GO_REF:0000033).

Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: catalytic activity captures part of Aldh1l1 biology, but a more specific replacement better represents the direct role (IEA, GO_REF:0000002).

Reason: catalytic activity is directionally related to Aldh1l1 but should be replaced by the more specific term(s): formyltetrahydrofolate dehydrogenase activity.

Proposed replacements: formyltetrahydrofolate dehydrogenase activity

Summary: Rat Aldh1l1 catalyzes NADP-dependent oxidation of free short-chain aldehydes as a secondary in-vitro capability.

Reason: The NADP-dependent aldehyde reaction is experimentally real, and the broad NAD(P)+ term permits NADP+ usage without requiring both cofactors. Its free-aldehyde substrate context is secondary to the established folate-formyl oxidation of the intact enzyme. The independent report supports this core/secondary distinction; retain the chemistry as non-core rather than remove or incorrectly replace a valid broader term.

Summary: The cytoplasm/cytosol is the principal established location of rat Aldh1l1.

Reason: Cytosolic one-carbon and folate metabolism is central to Aldh1l1 function. A cellular-component annotation can represent a core property even though it is not itself a molecular-function term. Retain the supported principal compartment as core.

Summary: The cytoplasm/cytosol is the principal established location of rat Aldh1l1.

Reason: Cytosolic one-carbon and folate metabolism is central to Aldh1l1 function. A cellular-component annotation can represent a core property even though it is not itself a molecular-function term. Retain the supported principal compartment as core.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining one-carbon metabolic process as a direct annotation (IEA, GO_REF:0000002). Falcon deep research places Aldh1l1 in folate-mediated one-carbon metabolism, catabolically removing one-carbon units from 10-formyl-THF and regenerating THF.

Reason: one-carbon metabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (IEA, GO_REF:0000120).

Reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IEA, GO_REF:0000120).

Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: oxidoreductase activity captures part of Aldh1l1 biology, but a more specific replacement better represents the direct role (IEA, GO_REF:0000002).

Reason: oxidoreductase activity is directionally related to Aldh1l1 but should be replaced by the more specific term(s): formyltetrahydrofolate dehydrogenase activity.

Proposed replacements: formyltetrahydrofolate dehydrogenase activity

Summary: The cytoplasm/cytosol is the principal established location of rat Aldh1l1.

Reason: Cytosolic one-carbon and folate metabolism is central to Aldh1l1 function. A cellular-component annotation can represent a core property even though it is not itself a molecular-function term. Retain the supported principal compartment as core.

Summary: Aldh1l1 clearly supports NADP-dependent aldehyde oxidation, but exclusion of all NAD+-dependent activity remains unresolved.

Reason: The ISO WITH/FROM is MGI:MGI:1340024, mouse Aldh1l1, which also contributes to the PAINT ancestor. NADP+ preference alone does not establish complete loss of NAD+ turnover. The available rat studies establish NADP-dependent chemistry; leave the NAD+-specific orthology assertion unresolved pending direct cofactor comparisons and inspection of the mouse assay. The independent OpenScientist report recommends rejection, but its own limitations explicitly acknowledge the absence of NAD+ kinetics rather than a formal negative result. PMID:17302434 explains NADP preference through a phosphate contact; this also does not establish zero NAD+ turnover. Retain UNDECIDED after adjudication, pending a direct cofactor assay.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining tetrahydrofolate interconversion as a direct annotation (ISO, GO_REF:0000121).

Reason: tetrahydrofolate interconversion is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (ISO, GO_REF:0000121).

Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (EXP, PMID:17302434). Falcon deep research confirms this is the canonical, primary molecular function.

Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (EXP, PMID:17884809).

Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (EXP, PMID:7822273).

Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (ISO, GO_REF:0000121).

Reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining NADPH regeneration as a direct annotation (ISO, GO_REF:0000121).

Reason: NADPH regeneration is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining NADPH regeneration as a direct annotation (IDA, PMID:1848231). Falcon deep research confirms the C-terminal ALDH domain oxidizes the formyl group to CO2 while reducing NADP+ to NADPH.

Reason: NADPH regeneration is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining folic acid metabolic process as a direct annotation (IDA, PMID:1848231).

Reason: folic acid metabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: The cytoplasm/cytosol is the principal established location of rat Aldh1l1.

Reason: Cytosolic one-carbon and folate metabolism is central to Aldh1l1 function. A cellular-component annotation can represent a core property even though it is not itself a molecular-function term. Retain the supported principal compartment as core.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (IMP, PMID:10585460). Falcon deep research frames Aldh1l1 as catabolically removing one-carbon units from 10-formyl-THF as CO2 while regenerating THF.

Reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining 10-formyltetrahydrofolate catabolic process as a direct annotation (IDA, PMID:1848231).

Reason: 10-formyltetrahydrofolate catabolic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IMP, PMID:10585460).

Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (IDA, PMID:1848231).

Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Rat Aldh1l1 catalyzes NADP-dependent oxidation of free short-chain aldehydes as a secondary in-vitro capability.

Reason: The NADP-dependent aldehyde reaction is experimentally real, and the broad NAD(P)+ term permits NADP+ usage without requiring both cofactors. Its free-aldehyde substrate context is secondary to the established folate-formyl oxidation of the intact enzyme. The independent report supports this core/secondary distinction; retain the chemistry as non-core rather than remove or incorrectly replace a valid broader term.

Summary: Rat FDH was isolated in an approximately 300-kDa assembly with CPS1 and BHMT using soybean trypsin inhibitor affinity chromatography.

Reason: The cited study concerns a co-purified FDH/CPS1/BHMT assembly, not merely the FDH homotetramer. Retain the experimental complex observation as non-core; the in-vitro gel-filtration assembly and SBTI interaction do not by themselves define the physiological core folate-enzyme complex.

Summary: The study detects FDH binding to soybean trypsin inhibitor and co-purification with CPS1/BHMT.

Reason: Retain this experimentally reported interaction context as non-core. The assay does not show that ordinary aldehyde oxidation or folate conversion depends on this assembled complex, and the generic complex-binding term should not be interpreted as evidence for a dedicated metabolic scaffold.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining formyltetrahydrofolate dehydrogenase activity as a direct annotation (TAS, PMID:14729668).

Reason: formyltetrahydrofolate dehydrogenase activity directly matches Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Aldh1l1's cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH supports retaining tetrahydrofolate biosynthetic process as a direct annotation (TAS, PMID:14729668).

Reason: tetrahydrofolate biosynthetic process is a direct process-level consequence of Aldh1l1's documented role in cytosolic 10-formyltetrahydrofolate oxidation to tetrahydrofolate, CO2, and NADPH.

Summary: Rat Aldh1l1 catalyzes NADP-dependent oxidation of free short-chain aldehydes as a secondary in-vitro capability.

Reason: The NADP-dependent aldehyde reaction is experimentally real, and the broad NAD(P)+ term permits NADP+ usage without requiring both cofactors. Its free-aldehyde substrate context is secondary to the established folate-formyl oxidation of the intact enzyme. The independent report supports this core/secondary distinction; retain the chemistry as non-core rather than remove or incorrectly replace a valid broader term.