Human Ferrochelatase: Insights for the Mechanism of Ferrous Iron Approaching Protoporphyrin IX by QM/MM and QTCP Free Energy Studies

Wu, Jingzhi; Wen, Sixiang; Zhou, Yiwei; Chao, Hui; Shen, Yong

doi:10.1021/acs.jcim.6b00216

Cited by 16 publications

(17 citation statements)

References 47 publications

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“…FECH is the final enzyme of the heme biosynthetic pathway, which catalyzes the insertion of ferrous iron into protoporphyrin IX (PPIX) to form heme. This pathway provides heme for hemoglobin and other vital hemoproteins 20‐22 . We showed that FECH mediates angiogenesis in vitro and in vivo 23 .…”

Section: Introductionmentioning

confidence: 81%

Ferrochelatase regulates retinal neovascularization

2020

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Ferrochelatase (FECH) is the terminal enzyme in heme biosynthesis. We previously showed that FECH is required for endothelial cell growth in vitro and choroidal neovascularization in vivo. But FECH has not been explored in retinal neovascularization, which underlies diseases like proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the inhibition of FECH using genetic and chemical approaches in the oxygen‐induced retinopathy (OIR) mouse model. In OIR mice, FECH expression is upregulated and co‐localized with neovascular tufts. Partial loss‐of‐function Fechm1Pas mutant mice showed reduced retinal neovascularization and endothelial cell proliferation in OIR. An intravitreal injection of the FECH inhibitor N‐methyl protoporphyrin had similar effects. Griseofulvin is an antifungal drug that inhibits FECH as an off‐target effect. Strikingly, intravitreal griseofulvin decreased both pathological tuft formation and areas of vasoobliteration compared to vehicle, suggesting potential as a FECH‐targeting therapy. Ocular toxicity studies revealed that intravitreal injection of griseofulvin in adult mice does not disrupt retinal vasculature, function, or morphology. In sum, mutation and chemical inhibition of Fech reduces retinal neovascularization and promotes physiological angiogenesis, suggesting a dual effect on vascular repair upon FECH inhibition, without ocular toxicity. These findings suggest that FECH inhibitors could be repurposed to treat retinal neovascularization.

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Section: Introductionmentioning

confidence: 81%

Ferrochelatase regulates retinal neovascularization

2020

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“…A [22][23][24][25]. In coproheme-LmCpfC, the distal histidine (His182) is H-bonded to Glu263, which form the amino acid pair, essential for metal binding and porphyrin deprotonation prior to ferrous iron insertion [26]. Therefore, the distal histidine is arrested and not able to deprotonate an incoming hydrogen peroxide molecule.…”

Section: Discussionmentioning

confidence: 99%

Crystal structures and calorimetry reveal catalytically relevant binding mode of coproporphyrin and coproheme in coproporphyrin ferrochelatase

et al. 2019

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Coproporphyrin ferrochelatases (CpfCs, EC 4.99.1.9) insert ferrous iron into coproporphyrin III yielding coproheme. CpfCs are utilized by prokaryotic, mainly monoderm (Gram-positive) bacteria within the recently detected coproporphyrin-dependent (CPD) heme biosynthesis pathway. Here, we present a comprehensive study on CpfC from Listeria monocytogenes (LmCpfC) including the first crystal structure of a coproheme-bound CpfC. Comparison of crystal structures of apo-LmCpfC and coproheme-LmCpfC allowed identification of structural rearrangements and of amino acids involved in tetrapyrrole macrocycle and Fe 2+ binding. Differential scanning calorimetry of apo-, coproporphyrin III-, and coproheme-LmCpfC underline the pronounced noncovalent interaction of both coproporphyrin and coproheme with the protein (DT m = 11°C compared to apo-LmCpfC), which includes the propionates (p2, p4, p6, p7) and the amino acids Arg29, Arg45, Tyr46, Ser53, and Tyr124. Furthermore, the thermodynamics and kinetics of coproporphyrin III and coproheme binding to apo-LmCpfC is presented as well as the kinetics of insertion of ferrous iron into coproporphyrin III-LmCpfC that immediately leads to formation of ferric coproheme-LmCpfC (k cat /K M = 4.7 9 10 5 M À1 Ás À1 ). We compare the crystal structure of coproheme-LmCpfC with available structures of CpfCs with artificial tetrapyrrole macrocycles and discuss our data on substrate binding, iron insertion and substrate release in the context of the CPD heme biosynthesis pathway.

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“…FECH is the final enzyme of the heme biosynthetic pathway, which catalyzes the insertion of ferrous iron into protoporphyrin IX (PPIX) to form heme. This pathway provides heme for hemoglobin and other vital hemoproteins (20)(21)(22). We showed that FECH mediates angiogenesis in vitro and in vivo (23).…”

Section: Introductionmentioning

confidence: 85%

Ferrochelatase regulates retinal neovascularization

Pasha

White

Corson

2020

Preprint

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Ferrochelatase (FECH) is the terminal enzyme in heme biosynthesis. We previously showed that FECH is required for endothelial cell growth in vitro and choroidal neovascularization in vivo. But FECH has not been explored in retinal neovascularization, which underlies diseases like proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the inhibition of FECH using genetic and chemical approaches in the oxygen-induced retinopathy (OIR) mouse model. In OIR mice, FECH expression is upregulated and co-localized with neovascular tufts. Partial loss-of-function Fechm1Pas mutant mice showed reduced retinal neovascularization and endothelial cell proliferation in OIR. An intravitreal injection of the FECH inhibitor N-methyl protoporphyrin had similar effects. Griseofulvin is an anti-fungal drug that inhibits FECH as an off-target effect. Strikingly, intravitreal griseofulvin blocked pathological tuft formation and revascularized areas of vasoobliteration faster than vehicle, suggesting potential as a FECH-targeting therapy. Ocular toxicity studies revealed that intravitreal injection of griseofulvin in adult mice does not disrupt retinal vasculature, function, or morphology. In sum, mutation and chemical inhibition of Fech reduces retinal neovascularization and promotes physiological angiogenesis, suggesting a dual effect on vascular repair upon FECH inhibition, without ocular toxicity. These findings suggest that FECH inhibitors could be repurposed to treat retinal neovascularization.

show abstract

Human Ferrochelatase: Insights for the Mechanism of Ferrous Iron Approaching Protoporphyrin IX by QM/MM and QTCP Free Energy Studies

Cited by 16 publications

References 47 publications

Ferrochelatase regulates retinal neovascularization

Ferrochelatase regulates retinal neovascularization

Crystal structures and calorimetry reveal catalytically relevant binding mode of coproporphyrin and coproheme in coproporphyrin ferrochelatase

Ferrochelatase regulates retinal neovascularization

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