Prolyl 4-Hydroxylase: Substrate Isosteres in Which an (<i>E</i>)- or (<i>Z</i>)-Alkene Replaces the Prolyl Peptide Bond

Vasta, James D.; Choudhary, Amit; Jensen, Katrina H.; McGrath, Nicholas A.; Raines, Ronald T.

doi:10.1021/acs.biochem.6b00976

Cited by 14 publications

(11 citation statements)

References 64 publications

(141 reference statements)

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“…26,30,31 The peptide bond of the Pro residue that is bound in the enzymic active site is likely in the cis (that is, E ) conformation. 32,33 After formation of the ferryl ion and subsequent hydroxylation of the Pro residue, the enzyme releases the nascent Hyp-containing strand and succinate.…”

Section: Cp4h Mechanismmentioning

confidence: 99%

Collagen Prolyl 4-Hydroxylase as a Therapeutic Target

Vasta

Raines

2018

J. Med. Chem.

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Collagen is the dominant protein of the extracellular matrix. Its distinguishing feature is a three-stranded helix of great tensile strength. (2 S,4 R)-4-Hydroxyproline residues are essential for the stability of this triple helix. These residues arise from the post-translational modification of (2 S)-proline residues by collagen prolyl 4-hydroxylases (CP4Hs), which are members of the Fe(II)- and α-ketoglutarate (AKG)-dependent dioxygenase family. Here, we provide a framework for the inhibition of CP4Hs as the basis for treating fibrotic diseases and cancer metastasis. We begin with a summary of the structure and enzymatic reaction mechanism of CP4Hs. Then, we review the metal ions, metal chelators, mimetics of AKG and collagen strands, and natural products that are known to inhibit CP4Hs. Our focus is on inhibitors with potential utility in the clinic. We conclude with a prospectus for more effective inhibitors.

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Section: Cp4h Mechanismmentioning

confidence: 99%

Collagen Prolyl 4-Hydroxylase as a Therapeutic Target

Vasta

Raines

2018

J. Med. Chem.

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“…Nonheme iron dioxygenases play an important role in all forms of life, where they take part in biochemical transformations, such as the biosynthesis of natural products and antibiotics as well as DNA repair mechanisms. − For instance, in mammals, 4-hydroxyproline is formed from proline on a nonheme iron dioxygenase, − while in plants the flavonol biosynthesis pathway includes a cascade of reactions by several nonheme iron dioxygenases that perform a selective substrate hydroxylation or desaturation reaction. − Among the class of nonheme iron dioxygenases are the group of ferrous iron/α-ketoglutarate-dependent dioxygenases that utilize α-ketoglutarate (αKG, also called 2-oxoglutarate) and dioxygen. − ,− They activate a range of substrates and catalyze a variety of chemical reactions comprising substrate hydroxylation, cyclization, halogenation, rearrangement, and desaturation, mostly centered on inactivated carbon centers of aliphatic groups. − …”

Section: Introductionmentioning

confidence: 99%

“…Many experimental and theoretical studies have been reported on the catalytic reaction mechanism of nonheme iron dioxygenases, − and a consensus mechanism involves the binding of dioxygen to the iron center followed by decarboxylation of αKG to form succinate and the formation of an iron(IV)-oxo species, which is believed to be the active oxidant. In this work, we investigated the hydrogen-atom abstraction pathways of l -Arg and l -homo-Arg from the C 3 - and C 4 -positions and the subsequent mechanisms leading to C 3 - and C 4 -hydroxylation and C 3 –C 4 -desaturation.…”

Section: Introductionmentioning

confidence: 99%

How Do Electrostatic Perturbations of the Protein Affect the Bifurcation Pathways of Substrate Hydroxylation versus Desaturation in the Nonheme Iron-Dependent Viomycin Biosynthesis Enzyme?

et al. 2021

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The viomycin biosynthesis enzyme VioC is a nonheme iron and α-ketoglutarate-dependent dioxygenase involved in the selective hydroxylation of L-arginine at the C 3position for antibiotics biosynthesis. Interestingly, experimental studies showed that using the substrate analogue, namely, L-homoarginine, a mixture of products was obtained originating from C 3hydroxylation, C 4 -hydroxylation, and C 3 −C 4 -desaturation. To understand how the addition of one CH 2 group to a substrate can lead to such a dramatic change in selectivity and activity, we decided to perform a computational study using quantum mechanical (QM) cluster models. We set up a large active-site cluster model of 245 atoms that includes the oxidant with its firstand second-coordination sphere influences as well as the substrate binding pocket. The model was validated against experimental work from the literature on related enzymes and previous computational studies. Thereafter, possible pathways leading to products and byproducts were investigated for a model containing L-Arg and one for L-homo-Arg as substrate. The calculated free energies of activation predict product distributions that match the experimental observation and give a low-energy C 3 -hydroxylation pathway for L-Arg, while for L-homo-Arg, several barriers are found to be close in energy leading to a mixture of products. We then analyzed the origins of the differences in product distributions using thermochemical, valence bond, and electrostatic models. Our studies show that the C 3 −H and C 4 −H bond strengths of L-Arg and Lhomo-Arg are similar; however, external perturbations from an induced electric field of the protein affect the relative C−H bond strengths of L-Arg dramatically and make the C 3 −H bond the weakest and guide the reaction to a selective C 3 -hydroxylation channel. Therefore, the charge distribution in the protein and the induced electric dipole field of the active site of VioC guides the L-Arg substrate activation to C 3 -hydroxylation and disfavors the C 4 -hydroxylation pathway, while this does not occur for L-homo-Arg. Tight substrate positioning and electrostatic perturbations from the second-coordination sphere residues in VioC also result in a slower overall reaction for L-Arg; however, they enable a high substrate selectivity. Our studies highlight the importance of the second-coordination sphere in proteins that position the substrate and oxidant, perturb charge distributions, and enable substrate selectivity.

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“…Following this study, they successfully extended the strategy to the synthesis of related analogs. ,− Finally, Raines synthesized cis- and trans- diproline isosteres and showed which conformation of the native peptidyl bond is preferentially recognized by collagen prolyl 4-hydroxylase. It also strengthened the idea that alkenes could be made use of as replacements for peptide bonds (Figure H) …”

Section: Introductionmentioning

confidence: 99%

Design of Pseudodiproline Dimers as Mimetics of Pro-Pro Units: Stereocontrolled Synthesis, Configurational Relevance, and Structural Properties

2021

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Stereocontrolled methods are described for the synthesis of hitherto unreported pseudodiproline dimers in which a cyclopentane carboxylic acid is linked to a pyrrolidine residue by a stereochemically defined hydroxymethylene tether. These prolinecyclopentane (Pro-Cyp) dimers have interesting structural characteristics as seen in their X-ray crystal structures as well as their nuclear magnetic resonance (NMR) spectra in CDCl 3 . They can be considered to be novel Pro-Pro mimetics, which can be used to replace natural diproline sequences with potential applications in medicinal chemistry. They also represent a new concept in the peptidomimetic design of chimeric proline-based amino acids as carbocyclic hydroxyethylene isosteres of inhibitor molecules, in which the stereodefined bridging hydroxyl group can simulate a tetrahedral intermediate in an enzyme complex.

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Prolyl 4-Hydroxylase: Substrate Isosteres in Which an (E)- or (Z)-Alkene Replaces the Prolyl Peptide Bond

Cited by 14 publications

References 64 publications

Collagen Prolyl 4-Hydroxylase as a Therapeutic Target

Collagen Prolyl 4-Hydroxylase as a Therapeutic Target

How Do Electrostatic Perturbations of the Protein Affect the Bifurcation Pathways of Substrate Hydroxylation versus Desaturation in the Nonheme Iron-Dependent Viomycin Biosynthesis Enzyme?

Design of Pseudodiproline Dimers as Mimetics of Pro-Pro Units: Stereocontrolled Synthesis, Configurational Relevance, and Structural Properties

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