| Aspect | Summary | Evidence/notes |
|---|---|---|
| Verified identity | **Rat Aldh1l1 / ALDH1L1 / FDH / 10-FTHFDH / cytosolic 10-formyltetrahydrofolate dehydrogenase**, EC **1.5.1.6**; UniProt target **P28037** matches the literature description of a **cytosolic** folate enzyme distinct from mitochondrial **ALDH1L2**. | Reviews consistently describe ALDH1L1 as the mammalian **cytosolic** 10-formyl-THF dehydrogenase and distinguish ALDH1L2 as the mitochondrial paralog with a leader peptide; ALDH1L2 is ~72% identical to ALDH1L1 and should not be conflated with rat ALDH1L1 (pqac-00000001, pqac-00000006, pqac-00000009, pqac-00000010). |
| Catalytic reaction | Overall reaction: **10-formyl-THF + NADP+ + H2O → THF + CO2 + NADPH + H+**. ALDH1L1 also has a **NADP+-independent hydrolase** activity releasing formate from 10-formyl-THF, but this is only part of the full coupled reaction. | The dehydrogenase reaction is the canonical, physiologically emphasized activity; the hydrolase activity proceeds at about **21%** of the dehydrogenase rate in recombinant enzyme studies. Functionally, the reaction **removes one-carbon units as CO2**, **replenishes THF**, and helps regulate **purine synthesis, histidine degradation, glycine synthesis, methylation flux, and formate clearance** (pqac-00000000, pqac-00000001, pqac-00000004, pqac-00000006, pqac-00000007). |
| Domain architecture | ALDH1L1 is a **multidomain/tetrameric fusion enzyme** of ~**902 aa** with ~**100 kDa** subunits: **N-terminal folate-binding/hydrolase domain** (~residues 1–310), **intermediate acyl-carrier-like linker** (~311–399/419), and **C-terminal ALDH-like dehydrogenase domain** (~400/420–902). | The enzyme is a natural fusion of folate-hydrolase, carrier, and ALDH modules; the **intermediate domain couples** the two catalytic centers and is essential for full FDH activity (pqac-00000001, pqac-00000002, pqac-00000004, pqac-00000006, pqac-00000020). |
| Key catalytic residues | **His106** and **Asp142** define the hydrolase active center; **Ser354** carries the **4′-phosphopantetheine (4′-PP)** prosthetic group; **Glu673** and **Cys707** are key ALDH-domain catalytic residues for the oxidative step. | Mutagenesis data: His106/Asp142 mutations abolish hydrolase and dehydrogenase activities; Glu673/Cys707 mutations abolish dehydrogenase while leaving hydrolase intact; Ser354 is the 4′-PP attachment site in the carrier domain (pqac-00000005, pqac-00000020). |
| Mechanistic steps | **Step 1:** N-terminal domain hydrolytically removes the formyl group from 10-formyl-THF. **Step 2:** The formyl group is transferred onto the **4′-PP swinging arm** attached to **Ser354** in the intermediate domain. **Step 3:** The C-terminal ALDH domain oxidizes the transferred formyl group to **CO2**, reducing **NADP+ → NADPH**. | The 4′-PP arm extends ~**20 Å**; the ALDH catalytic center lies at the end of a ~**12 Å** tunnel, supporting the carrier-mediated channeling model. The hydrolase step must precede dehydrogenase catalysis (pqac-00000005, pqac-00000006, pqac-00000020). |
| Subcellular localization | **Cytosolic/cytoplasmic** enzyme; part of the **cytosolic folate/one-carbon pathway**. Not the mitochondrial enzyme. | Cytosolic localization is a core identifier throughout the FDH/ALDH1L1 literature; mitochondrial one-carbon oxidation to CO2 is carried out by **ALDH1L2**, not ALDH1L1 (pqac-00000000, pqac-00000001, pqac-00000002, pqac-00000006, pqac-00000017). |
| Tissue expression highlights | Highly expressed in **liver, kidney, pancreas**; in rat liver cytosol ALDH1L1 can comprise about **1.2% of total cytosolic protein**, indicating an unusually abundant metabolic enzyme. | Reviews report highest mRNA/protein abundance in liver/kidney/pancreas and absent/undetectable expression in several other tissues (e.g., placenta, spleen, thymus, small intestine, leukocytes, testis, ovary in cited surveys). Rat liver abundance (~1.2%) is repeatedly noted (pqac-00000000, pqac-00000001, pqac-00000012). |
| Brain / astrocyte relevance | ALDH1L1 is widely used as a **pan-astrocyte marker/promoter** in neuroscience, although this reflects expression pattern rather than the primary enzymatic function. In developing brain, ALDH1L1 is associated with **quiescent** rather than proliferating cells. | Modern astrocyte studies use **Aldh1l1-EGFP/Rpl10a** and **Aldh1l1-Cre/ERT2** tools for cell-type-specific profiling/manipulation; reviews and experimental papers note ALDH1L1 as broader astrocyte coverage than GFAP in many CNS settings (pqac-00000010, pqac-00000016, pqac-00000019). |
| Quantitative functional phenotypes | Loss of ALDH1L1 perturbs folate-linked metabolism: in mouse liver **FIGLU increased >15-fold** and liver total folate decreased by ~**1.2-fold (males)** / ~**1.4-fold (females)**; in RT4 cancer cells ALDH1L1 loss caused an ~**8-fold decrease in glycine**. | These quantitative studies support ALDH1L1 as a regulator of **THF availability**, **glycine production**, **histidine degradation**, and **methylation-linked metabolism**, even when gross phenotypes are mild (pqac-00000003, pqac-00000008, pqac-00000011). |
| Pathway role | ALDH1L1 functions in **folate-mediated one-carbon metabolism**, especially catabolic removal of 1C units from **10-formyl-THF** and regeneration of **THF** for interconnected pathways. | Expert interpretation: ALDH1L1 can limit flux into folate-dependent biosynthesis while sustaining THF-dependent reactions; it is linked to **formate detoxification/clearance**, **purine biosynthesis control**, **glycine synthesis from serine**, and **cellular methylation status** (pqac-00000000, pqac-00000002, pqac-00000007, pqac-00000018). |
| Disease relevance: cancer | ALDH1L1 is widely viewed as a **candidate tumor suppressor/metabolic brake** and is frequently **downregulated or silenced** in cancers, often via **promoter/CpG island methylation**. Re-expression in cancer cells is antiproliferative. | Quantitative methylation detail: reported **76–95% CpG methylation** in cancer cell lines; decreased expression is associated with more aggressive disease in several tumor contexts, while re-expression can induce **cell-cycle arrest/apoptosis** (pqac-00000009, pqac-00000012, pqac-00000013, pqac-00000015). |
| Biomedical applications | **Functional annotation:** marker of cytosolic folate catabolism and THF regeneration. **Research tool:** Aldh1l1 promoter-driven reporter/TRAP/Cre lines for astrocyte profiling. **Translational interest:** epigenetic status and metabolic consequences of ALDH1L1 loss in cancer. | Useful both as a mechanistically defined folate enzyme and as a practical cell-type handle in neurobiology; however, astrocyte-tool use should not be mistaken for a change in the enzyme’s core biochemical identity (pqac-00000008, pqac-00000016, pqac-00000019). |


*Table: This table condenses the verified identity, enzymatic mechanism, localization, expression, and biomedical relevance of rat ALDH1L1 (UniProt P28037). It is designed as a quick reference for functional annotation and literature-grounded interpretation.*