scholarly journals NCOA4 Mediates Mobilization of Hepatic Iron Stores after Blood Loss

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1046-1046
Author(s):  
Xiuqi Li ◽  
Larisa Lozovatsky ◽  
Dong Liu ◽  
Nadia Ayala-Lopez ◽  
Karin E. Finberg
Keyword(s):  
Blood Loss ◽  
Heme Iron ◽  
Hepatic Iron ◽  
Dietary Iron ◽  
Acute Blood Loss ◽  
Treatment Groups ◽  
Iron Stores ◽  
Iron Mobilization ◽  
Non Heme Iron

Abstract The intracellular protein NCOA4 mediates the autophagic degradation of ferritin in vitro (Mancias et al., Nature 2014; Dowdle et al., Nat Cell Biol 2014); mice with global Ncoa4 disruption show hyperferremia, microcytic anemia, and ferritin accumulation in multiple organs, including liver (Bellelli et al., Cell Rep 2016). Here, we dissect the requirement for NCOA4 in hepatic iron mobilization after acute blood loss, using Ncoa4-targeting siRNA that was conjugated to triantennary N-acetylgalactosamine (GalNAc-Ncoa4 siRNA) to promote uptake by hepatocytes. On experimental day 0, 8-week-old female C57BL/6N mice underwent a single 500 μl phlebotomy, which was followed immediately by intraperitoneal volume replacement (saline) and concomitant subcutaneous injection of either GalNAc-Ncoa4 siRNA (3 mg/kg) or saline vehicle. The phlebotomized mice then underwent a second, terminal blood collection and organ harvest at either 3 days later (when mice subjected to this phlebotomy protocol are known to reach their hematocrit nadir) or 7 days later (when mice subjected to this phlebotomy protocol are known to exhibit substantial hematocrit recovery). To provide an experimental baseline, a group of 8-week-old mice that were not phlebotomized and did not receive a subcutaneous injection of either saline or GalNAc-Ncoa4-siRNA were analyzed on experimental day 0. Injection of GalNAc-Ncoa4 siRNA immediately after phlebotomy resulted in marked hepatic Ncoa4 knockdown at both 3 and 7 days after phlebotomy. Compared to non-phlebotomized mice (NPM), phlebotomized mice (PM) treated with either saline or GalNAc-Ncoa4 siRNA showed similar reductions in red blood cell count, hemoglobin concentration, and hematocrit at day 3, confirming that similar blood volumes were removed. Compared to NPM, PM treated with saline showed significantly lower levels of ferritin subunits by immunoblotting of liver lysates, consistent with a model in which phlebotomy induces the degradation of ferritin complexes in hepatocytes. By contrast, in PM treated with GalNAc-Ncoa4 siRNA, hepatic ferritin subunit levels did not decrease after blood loss, and at post-phlebotomy day 7, hepatic ferritin subunit levels were significantly higher in PM treated with GalNAc-Ncoa4 siRNA than in PM treated with saline. By post-phlebotomy day 7, mean liver non-heme iron concentration (LIC) was also significantly lower in PM injected with saline compared to NPM, suggesting that non-heme iron had been mobilized from their livers in the setting of increased iron demand for erythropoiesis. By contrast, in PM treated with GalNAc-Ncoa4 siRNA, mean LIC failed to decrease after phlebotomy. Hepatic Tfrc mRNA and protein were upregulated in PM treated GalNAc-Ncoa4 siRNA compared to saline, suggesting that an acute reduction in NCOA4 activity reduces cytosolic iron levels in hepatocytes. Interestingly, when compared to NPM, saline-treated PM showed a trend towards higher hepatic Ncoa4 mRNA when assessed at either day 3 (P=0.09) or day 7 (P=0.06) after blood loss, raising the possibility that hepatic NCOA4 requirements increase in response to phlebotomy. Although phlebotomy failed to lower hepatic iron stores in PM with hepatocellular Ncoa4 knockdown, hematological recovery at day 7 was similar in both treatment groups. At day 7 after phlebotomy, splenic non-heme iron stores were similarly depleted in both treatment groups. Interestingly, compared to PM treated with saline, PM treated with GalNAc-Ncoa4 siRNA showed lower hepatic hepcidin expression at day 7, raising the possibility that greater dietary iron absorption may compensate for the lack of hepatic iron mobilization in this group to allow for normal hematological recovery. Collectively, these findings suggest that NCOA4 activity is required to mobilize iron from the liver when extrahepatic iron demands increase following acute blood loss. However, in our model with hepatocellular Ncoa4 knockdown, dietary iron uptake and/or iron release from extrahepatic storage sites may compensate for the lack of hepatic iron mobilization to support stress erythropoiesis. While ferritin degradation has been shown to occur through both lysosomal and proteasomal pathways in vitro, our findings suggest that if NCOA4 expression is reduced following acute blood loss, other cellular pathways in hepatocytes cannot compensate to mobilize iron from the liver. Disclosures No relevant conflicts of interest to declare.

scholarly journals NCOA4 is Regulated by HIF and Mediates Mobilization of Murine Hepatic Iron Stores After Blood Loss

Blood ◽  
2020 ◽  
Author(s):  
Xiuqi Li ◽  
Larisa Lozovatsky ◽  
Abitha Sukumaran ◽  
Luis Gonzalez ◽  
Anisha Jain ◽  
...  
Keyword(s):  
Blood Loss ◽  
Iron Homeostasis ◽  
Hepatoma Cell ◽  
Iron Concentration ◽  
Heme Iron ◽  
Hepatic Iron ◽  
Prolyl Hydroxylases ◽  
Iron Stores ◽  
Mrna Induction ◽  
Non Heme Iron

The mechanisms by which phlebotomy promotes the mobilization of hepatic iron stores are not well understood. NCOA4 (nuclear receptor coactivator 4) is a widely-expressed intracellular protein previously shown to mediate the autophagic degradation of ferritin. Here, we investigate a local requirement for NCOA4 in the regulation of hepatic iron stores and examine mechanisms of NCOA4 regulation. Hepatocyte-targeted Ncoa4 knockdown in non-phlebotomized mice had only modest effects on hepatic ferritin subunit levels and non-heme iron concentration. After phlebotomy, mice with hepatocyte-targeted Ncoa4 knockdown exhibited anemia and hypoferremia similar to control mice with intact Ncoa4 regulation, but showed a markedly impaired ability to lower hepatic ferritin subunit levels and hepatic non-heme iron concentration. This impaired hepatic response was observed even when dietary iron was limited. In both human and murine hepatoma cell lines, treatment with chemicals that stabilize hypoxia inducible factor (HIF), including desferrioxamine, cobalt chloride, and dimethyloxalylglycine, raised NCOA4 mRNA. This NCOA4 mRNA induction occurred within 3 hours, preceded a rise in NCOA4 protein, and was attenuated in the setting of dual HIF-1a and HIF-2a knockdown. In summary, we show for the first time that NCOA4 plays a local role in facilitating iron mobilization from the liver after blood loss and that HIF regulates NCOA4 expression in cells of hepatic origin. Because the prolyl hydroxylases that regulate HIF stability are oxygen and iron-dependent enzymes, our findings suggest a novel mechanism by which hypoxia and iron deficiency may modulate NCOA4 expression to impact iron homeostasis.

scholarly journals NCOA4 Expression in Hepatic Cells Is Upregulated Under Physiological and Pathophysiological Conditions Associated with Hypoxia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 431-431
Author(s):  
Xiuqi Li ◽  
Larisa Lozovatsky ◽  
Karin E. Finberg
Keyword(s):  
Hepatoma Cell ◽  
Fold Increase ◽  
Heme Iron ◽  
Hepatoma Cell Line ◽  
Hepatic Iron ◽  
Mrna Levels ◽  
Iron Stores ◽  
Pregnant Females ◽  
Non Heme Iron ◽  
Hep3b Cells

The ubiquitously expressed intracellular protein NCOA4 mediates the degradation of ferritin in vitro (Mancias et al., Nature 2014; Dowdle et al., Nat Cell Biol 2014) and its loss disrupts systemic iron balance in mice (Bellelli et al., Cell Rep 2016). While a mechanism for increased NCOA4 protein turnover under high iron conditions has been reported in transformed cell lines of non-hepatic origin (Mancias et al., Elife, 2015), factors that regulate NCOA4 mRNA levels have not yet been described. Here we investigate stimuli that induce NCOA4 mRNA expression in hepatoma cells as well as in liver, the major iron depot of the body. We found that treating the human hepatoma cell line, Hep3B, for 18 hrs with increasing concentrations of the iron chelator desferrioxamine (DFO; 25-100μM) resulted in significantly higher NCOA4 mRNA (ANOVA P<.0001; 1.8 fold increase at the highest dose). Additionally, the murine hepatoma cell line, Hepa1-6, responded to 18 hrs of DFO treatment (25-100μM) with a dose-dependent rise in Ncoa4 mRNA levels (ANOVA P<.0001; 2.7 fold increase at the highest dose). DFO treatment of Hep3B and Hepa1-6 cells also increased mRNA levels of the transferrin receptor, confirming induction of iron deficiency. Because DFO has also been shown to stabilize hypoxia inducible factor (HIF), we examined the effects of other chemical hypoxia mimetics on hepatoma cell lines. Hep3B cells treated for 18 hrs with CoCl2 (25-75 μM), which is known to enhance the stability of HIF1α, showed a 2-fold increase in NCOA4 mRNA (ANOVA; P<.0001). Similarly, treatment of Hep3B cells with dimethyloxalylglycine (DMOG; 1mM), a competitive inhibitor of HIF prolyl-hydroxylases that promote HIF-α degradation, resulted in a 3-fold increase in NCOA4 mRNA at 12 hrs, which was further enhanced at 18 hrs. These results suggest that hepatoma cells in culture may respond to decreased iron availability and/or hypoxia by upregulating NCOA4 mRNA levels. We also investigated if Ncoa4 mRNA expression is upregulated in mouse livers under conditions associated with depletion of hepatic iron stores and/or hypoxia. C57BL/6N mice raised on a 45 p.p.m. iron diet were subjected to a large-volume phlebotomy (500μl; accompanied by intraperitoneal saline volume replacement) and fed an iron-deficient diet (2-6 p.p.m.) after bleeding. Seven days after phlebotomy, mice showed significantly lower blood hemoglobin levels (Student's T test P<.0001) and hepatic non-heme iron concentrations (P<.0001). However, the phlebotomized mice exhibited 1.8-fold higher hepatic Ncoa4 mRNA levels (P<.01) compared to non-phlebotomized controls. Additionally, we examined if hepatic Ncoa4 expression changed during normal pregnancy, a state in which extra-hepatic iron demands are increased by both the expanding maternal blood volume and the growing fetus. Compared to non-pregnant females, C57BL/6N mice at day 18.5 of pregnancy showed significantly lower liver non-heme iron concentrations (P<.01), while hepatic Ncoa4 mRNA levels were 3.5-fold higher (P<.01) in pregnant females compared to non-pregnant controls. By mining a published murine gene expression dataset (GEO accession GDS5818), we found that hepatic Ncoa4 mRNA levels are relatively high in early life (embryonic day 18 and postnatal day 5) and decline by adulthood (postnatal day 56), suggesting a relatively greater hepatic requirement for NCOA4 function during periods of high growth. Collectively, these in vivo data show that Ncoa4 upregulation correlates with conditions in which mobilizing iron for systemic use takes precedence over building hepatic iron stores. In summary, we show for the first time that Ncoa4 mRNA rises significantly in physiological and pathophysiological states in which increased extra-hepatic iron demands induce a reduction in hepatic iron stores. Additionally, we show that Ncoa4 mRNA levels in cultured cells of hepatic origin rise in response to hypoxia mimetics. Because NCOA4 functions as a cargo receptor that traffics ferritin to the autolysosome, NCOA4 protein is expected to be consumed during the process of ferritinophagy. We suggest that upregulation of hepatic Ncoa4 mRNA in response to hypoxia may represent a physiological adaptation to replenish NCOA4 protein that is needed to support continued mobilization of iron from the liver during periods of increased systemic iron demands. Disclosures No relevant conflicts of interest to declare.

scholarly journals Dietary intake of heme iron is associated with ferritin and hemoglobin levels in Dutch blood donors: results from Donor InSight

Haematologica ◽  
2019 ◽  
Vol 105 (10) ◽  
pp. 2400-2406
Author(s):  
Tiffany C. Timmer ◽  
Rosa de Groot ◽  
Judith J.M. Rijnhart ◽  
Jeroen Lakerveld ◽  
Johannes Brug ◽  
...  
Keyword(s):  
Physical Activity ◽  
Blood Donors ◽  
Blood Donation ◽  
Vigorous Physical Activity ◽  
Heme Iron ◽  
Dietary Iron ◽  
Iron Intake ◽  
Men And Women ◽  
Iron Stores ◽  
Non Heme Iron

Whole blood donors, especially frequently donating donors, have a risk of iron deficiency and low hemoglobin levels, which may affect their health and eligibility to donate. Lifestyle behaviors, such as dietary iron intake and physical activity, may influence iron stores and thereby hemoglobin levels. We aimed to investigate whether dietary iron intake and questionnaire-based moderate-to-vigorous physical activity were associated with hemoglobin levels, and whether ferritin levels mediated these associations. In Donor InSight-III, a Dutch cohort study of blood and plasma donors, data on heme and non-heme iron intake (mg/day), moderate-to-vigorous physical activity (10 minutes/day), hemoglobin levels (mmol/L) and ferritin levels (μg/L) were available in 2,323 donors (1,074 male). Donors with higher heme iron intakes (regression coefficients (β) in men and women: 0.160 and 0.065 mmol/L higher hemoglobin per 1 mg of heme iron, respectively) and lower non-heme iron intakes (β: -0.014 and -0.017, respectively) had higher hemoglobin levels, adjusted for relevant confounders. Ferritin levels mediated these associations (indirect effect (95% confidence interval) in men and women respectively: 0.074 (0.045; 0.111) and 0.061 (0.030; 0.096) for heme and -0.003 (-0.008;0.001) and -0.008 (-0.013;-0.003) for non-heme). Moderate-to-vigorous physical activity was negatively associated with hemoglobin levels in men only (β: -0.005), but not mediated by ferritin levels. In conclusion, higher heme and lower non-heme iron intake were associated with higher hemoglobin levels in donors, via higher ferritin levels. This indicates that donors with high heme iron intake may be more capable of maintaining iron stores to recover hemoglobin levels after blood donation.

The Precision of in vitro Methods and Algorithms for Predicting the Bioavailability of Dietary Iron

2005 ◽  
Vol 75 (6) ◽  
pp. 436-445 ◽  
Author(s):  
Sean Lynch
Keyword(s):  
Iron Absorption ◽  
Heme Iron ◽  
Iron Bioavailability ◽  
Cell Uptake ◽  
In Vitro Tests ◽  
Cellular Iron ◽  
Non Heme Iron ◽  
Human Volunteers ◽  
Dialyzable Iron

Three factors determine how much iron will be absorbed from a meal. They are the physiological mechanisms that regulate uptake by and transfer through the enterocytes in the upper small intestine, the quantity of iron in the meal, and its availability to the cellular iron transporters. Established methods exist for predicting the effect of physiological regulation and for measuring or estimating meal iron content. Three approaches to estimating bioavailability have been advocated. Two are in vitro screening procedures: measurement of dialyzable iron and Caco-2 cell uptake, both carried out after in vitro simulated gastric and pancreatic digestion. The third is the use of algorithms based on the predicted effects of specific meal components on absorption derived from isotopic studies in human volunteers. The in vitro procedures have been very useful for identifying and characterizing factors that affect non-heme iron absorption, but direct comparisons between absorption predicted from the in vitro tests and measurements in human volunteers have only been made in a limited number of published studies. The available data indicate that dialysis and Caco-2 cell uptake are useful for ranking meals and single food items in terms of predicted iron bioavailability, but may not reflect the magnitudes of the effects of factors that influence absorption accurately. Algorithms based on estimates of the amounts of heme iron and of enhancers and inhibitors of non-heme iron absorption in foods make it possible to classify meals or diets as being of high, medium, or low bioavailability. The precision with which meal iron bioavailability can be predicted in a population, for which a specific algorithm has been developed, is improved by measuring the content of the most important enhancers and inhibitors. However, the accuracy of such predictions appears to be much lower when the algorithm is applied to meals eaten by different populations.

Ex Vivo Production of Transfusable Red Blood Cells at Large Scale from Cord Blood CD34+ Cells Using a Coculture System with Human Telomerase Catalytic Subunit (hTERT)-Transfected Human Stromal Cells at Early Phase and with Acitivated Macrophage from Cord Blood CD34+ Cells at Late Phase.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2701-2701
Author(s):  
Akihito Fujimi ◽  
Takuya Matsunaga ◽  
Masayoshi Kobune ◽  
Yutaka Kawano ◽  
Ikuta Tanaka ◽  
...  
Keyword(s):  
Blood Loss ◽  
Cord Blood ◽  
Stromal Cells ◽  
Blood Cells ◽  
Large Scale ◽  
Acute Blood Loss ◽  
Cd34 Cells ◽  
Cord Blood Cd34 ◽  
Human Stromal Cells

Abstract New sources of red blood cells (RBC) would improve the transfusion capacity of blood centers. Several investigators have previously reported that erythroblasts could be obtained from hematopoietic stem cells including those of cord blood (CB) by in vitro culture. However, transfusion of erythroblasts may not be suitable for supplementation of acute blood loss because it should need some time lag until hemoglobin (RBC) boost in circulation due to the fact that transfused erythroblasts once lodged at bone marrow where they undergo maturation into RBCs which are bound to be released into circulation. We have developed a culture system for producing large quantity of enucleated RBCs (e-RBCs) as well as erythroblasts from CB in vitro: one unit e-RBCs (2 x 1012 RBCs) was obtained from one standard CB unit (corresponding to 2 x 106 CD34+ cells) using a coculture system with hTERT-transfected human stromal cells at early phase followed by with activated macrophage in liquid culture (American Society of Hematology 45th Annual Meeting, SanDiego, 2003). In the present study, we first analyzed the function of those manufactured e-RBCs in comparison of that of adult peripheral blood RBCs (PB-RBCs) or that of eryhthroblasts. The hemoglobin (Hb) content of the e-RBCs quantified by photometric determination was almost equivalent to that of adult PBRBC. A Hb A/Hb F ratio of e-RBC analyzed by high-performance liquid chromatography (HbA: HbF = 35: 65) was between those of CB RBCs (10: 90) and adult PB-RBC (99: 1). Oxygen dissociation curves of e-RBCs measured by Hemox-Analyzer was comparable to that of fresh adult PB-RBCs. The erythroblasts showed adhesive property to stromal cells in vitro but e-RBC did not. When we injected e-RBCs into NOD/SCID mice, they were detectable in circulation while erythroblasts were not. In conclusion, the e-RBCs produced by large-scale culturing system from CB CD34+ cells may be useful for acute blood loss.

scholarly journals Oral Administration of Ginger-Derived Lipid Nanoparticles and Dmt1 siRNA Potentiates the Effect of Dietary Iron Restriction and Mitigates Pre-Existing Iron Overload in Hamp KO Mice

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1686
Author(s):  
Xiaoyu Wang ◽  
Mingzhen Zhang ◽  
Regina R. Woloshun ◽  
Yang Yu ◽  
Jennifer K. Lee ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Heme Iron ◽  
Dietary Iron ◽  
Iron Loading ◽  
Body Iron ◽  
Iron Restriction ◽  
Sirna Treatment ◽  
Non Heme Iron

Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and >85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40–50%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH.

scholarly journals Characterization of non-heme iron aliphatic halogenase WelO5* from Hapalosiphon welwitschii IC-52-3: Identification of a minimal protein sequence motif that confers enzymatic chlorination specificity in the biosynthesis of welwitindolelinones

2017 ◽  
Vol 13 ◽  
pp. 1168-1173 ◽  
Author(s):  
Qin Zhu ◽  
Xinyu Liu
Keyword(s):  
Biochemical Characterization ◽  
Structural Diversity ◽  
Heme Iron ◽  
Sequence Motif ◽  
Rational Engineering ◽  
Non Heme Iron ◽  
C Terminus ◽  
Signature Sequence

The in vitro biochemical characterization revealed that iron/2-oxoglutarate (Fe/2OG)-dependent aliphatic halogenase WelO5* in Hapalosiphon welwitschii IC-52-3 has an enhanced substrate specificity towards 12-epi-hapalindole C (1) in comparison to WelO5 in H. welwitschii UTEX B1830. This allowed us to define the origin of the varied chlorinated versus dechlorinated alkaloid structural diversity between the two welwitindolinone producers. Furthermore, this study, along with the recent characterization of the AmbO5 protein, collectively confirmed the presence of a signature sequence motif in the C-terminus of this newly discovered halogenase enzyme family that confers substrate promiscuity and specificity. These observations may guide the rational engineering and evolution of these proteins for biocatalyst application.

scholarly journals Molecular insights into the unusually promiscuous and catalytically versatile Fe(II)/α-ketoglutarate-dependent oxygenase SptF

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Hui Tao ◽  
Takahiro Mori ◽  
Heping Chen ◽  
Shuang Lyu ◽  
Akihito Nonoyama ◽  
...  
Keyword(s):  
High Efficiency ◽  
Cyclopropane Ring ◽  
Heme Iron ◽  
Oxidation Reactions ◽  
Loop Region ◽  
Non Heme Iron ◽  
Vitro Analysis ◽  
Continuous Oxidation ◽  
In Vitro Analysis

AbstractNon-heme iron and α-ketoglutarate-dependent (Fe/αKG) oxygenases catalyze various oxidative biotransformations. Due to their catalytic flexibility and high efficiency, Fe/αKG oxygenases have attracted keen attention for their application as biocatalysts. Here, we report the biochemical and structural characterizations of the unusually promiscuous and catalytically versatile Fe/αKG oxygenase SptF, involved in the biosynthesis of fungal meroterpenoid emervaridones. The in vitro analysis revealed that SptF catalyzes several continuous oxidation reactions, including hydroxylation, desaturation, epoxidation, and skeletal rearrangement. SptF exhibits extremely broad substrate specificity toward various meroterpenoids, and efficiently produced unique cyclopropane-ring-fused 5/3/5/5/6/6 and 5/3/6/6/6 scaffolds from terretonins. Moreover, SptF also hydroxylates steroids, including androsterone, testosterone, and progesterone, with different regiospecificities. Crystallographic and structure-based mutagenesis studies of SptF revealed the molecular basis of the enzyme reactions, and suggested that the malleability of the loop region contributes to the remarkable substrate promiscuity. SptF exhibits great potential as a promising biocatalyst for oxidation reactions.

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