Falcon deep research report (Edison Scientific) for Danio rerio hif1an / FIH-1 (P59723)
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Hif1an/FIH-1 is a JmjC/cupin-fold Fe(II)/2-oxoglutarate-dependent dioxygenase (non-heme iron oxygenase)
acting as an oxygen-sensitive regulator of HIF transcriptional activity; this is its core catalytic identity.
"FIH (gene: **HIF1AN/hif1an**) is a **JmjC/cupin-fold Fe(II)/2-OG-dependent dioxygenase** (non-heme iron oxygenase) functioning as an oxygen-sensitive regulator of hypoxia-inducible factor (HIF) transcriptional activity."
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The canonical substrate is the conserved C-terminal transactivation domain asparagine of HIF-alpha
(HIF-1alpha Asn803); hydroxylation blocks p300/CBP coactivator recruitment and represses HIF transcription
without changing HIF-alpha abundance.
"FIH hydroxylates a conserved asparagine in the **C-terminal transactivation domain (C-TAD)**—classically **HIF-1α Asn803** (and the analogous HIF-2α site). This hydroxylation blocks recruitment of transcriptional co-activators **p300/CBP**, thereby repressing HIF-driven transcription without necessarily changing HIF-α abundance."
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Catalysis requires Fe(II), O2, 2-oxoglutarate and typically a reductant such as ascorbate, with ordered
cofactor/substrate binding (Fe2+ then 2-OG then peptide then O2), consistent with ferrous iron binding and
2-OG/carboxylic acid binding annotations.
"catalysis requires **Fe(II)**, **O2**, **2-OG**, and typically a **reductant such as ascorbate** to maintain iron in the reduced state."
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In zebrafish, Fih-1 is a negative regulator of HIF/VEGF-A-driven angiogenesis: loss of fih-1 increases
vegf-aa165 and induces ectopic intersegmental-vessel sprouts, while overexpression suppresses ISV formation
(rescued by vegf-aa165), placing Fih-1 upstream of VEGF-A signaling.
"Loss of fih-1 function increases expression of **vegf-aa165** and induces **exuberant ectopic sprouts** from **intersegmental vessels (ISVs)**, whereas fih-1 overexpression suppresses ISV formation; suppression is rescued by co-expression of vegf-aa165, functionally positioning Fih-1 upstream of VEGF-A-driven angiogenesis."
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FIH is predominantly cytoplasmic in vertebrate cells, and in zebrafish-related assays FIH-1 colocalizes with
the E3 ligase Mindbomb (Mib1) in the perinuclear region, supporting cytoplasmic and perinuclear localization.
"In zebrafish-related cell assays, FIH-1 and the E3 ligase Mindbomb (Mib1) were reported to **colocalize in the perinuclear region**, consistent with a cytoplasmic/perinuclear pool relevant for signaling and protein interaction."
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Beyond HIF, FIH hydroxylates ankyrin-repeat domain (ARD) proteins as a major non-HIF substrate class,
consistent with peptidyl-Asn/Asp/His dioxygenase activity; however these non-HIF targets are conserved
vertebrate hypotheses not directly validated in Danio rerio.
"A major class of non-HIF substrates are **ankyrin repeat domain (ARD)** proteins; a proposed degenerate recognition motif has been summarized as **LXXXXX[D/E]VN**, but structural context and accessibility strongly condition hydroxylation efficiency."
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Functional conservation in fish is high; the zebrafish JmjC catalytic region was reported as 96% homologous
to human FIH, supporting ISS transfer of the human FIH catalytic and cofactor functions to zebrafish hif1an.
"zebrafish enzymatic JmjC region was reported as **96% homologous** to human FIH."