# Reactivity of Manganese and Iron Metalloenzyme Models > **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $291,159 ## Abstract Project Summary Heme proteins participate in many essential biological processes that are important to human health and disease, and they are targets of both diagnostic and therapeutic treatments. An important subset of these proteins are enzymes that activate dioxygen (O2) or its reduced analogs (e.g. H2O2). These enzymes utilize the same iron cofactor to mediate a wide range of reactions, including mono- and dioxygenation of organic substrates, C-H activation, desaturation, and C-C bond cleavage. How nature tunes the metal center and active site of these enzymes to mediate such a wide range of functionality is a question of fundamental significance that continues to motivate significant research. This proposal focuses on the synthesis and reactivity of small- molecule model complexes of key intermediates, and their related bond-making/bond-breaking events, proposed in the mechanisms of the thiolate-ligated heme enzymes Cytochrome P450 (CYP), chloroperoxidase (CPO), and aromatic peroxygenase (APO), and the non-thiolate-ligated heme dioxygenases tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO). The thiolate-ligated heme enzymes are capable of oxidizing hydrocarbon C-H bonds, and the proposed mechanism involves H-atom transfer (HAT) (proton-coupled electron- transfer, PCET) from R-H to an intermediate called Compound-I (Fe=O), followed by hydroxyl transfer (“rebound”) from protonated Compound-II (Fe-OH) to give the ROH product. However, the rebound step can be diverted to other pathways, leading to distinctly different reaction outcomes. Many questions remain regarding the fundamental structural, electronic, thermodynamic and kinetic factors that control both HAT and rebound steps. In contrast, TDO/IDO are proposed to rely on an Fe(O2) adduct and Compound-II as active oxidants, although much remains to be learned about this mechanism. Efforts in this proposal will address these questions through the synthesis and study of biomimetic M=O, M-OH, and M-O2 species that will be prepared with tailored porphyrinoid ligands designed to stabilize these species and allow for their direct study. These ligands include ring-contracted corroles (Crl) and corrolazines (Cz), which have a modified porphyrin nucleus which presents a trianionic (3-) charge to the metal, similar to a thiolate-ligated heme active site. Our previous efforts showed that the Crl and Cz platforms provide access to novel species not seen with conventional porphyrins, including a Cpd-I analog with the same spin ground state as found in CYP and CPO, and the first example of a protonated Cpd-II model. Systematic modifications can be made to these small-molecule models through established synthetic methodologies, providing atomic-level control over their geometric/electronic structures, and providing a means to establish structure-function relationships that can be challenging or impossible to obtain when studying the enzymes alone. The long-term goals of the proposed wor... ## Key facts - **NIH application ID:** 10442664 - **Project number:** 5R01GM101153-10 - **Recipient organization:** JOHNS HOPKINS UNIVERSITY - **Principal Investigator:** David P Goldberg - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $291,159 - **Award type:** 5 - **Project period:** 2013-09-01 → 2025-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10442664 ## Citation > US National Institutes of Health, RePORTER application 10442664, Reactivity of Manganese and Iron Metalloenzyme Models (5R01GM101153-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10442664. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*