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Metalloenzymes may contain single metal ions, such as iron or copper, bound to the protein directly or through an organic ligand that chelates the metal, such as porphyrins (heme). Transition metals are especially useful catalytic centers because they can access multiple oxidation states with redox potentials that are tuned by the organic ligand or protein environment to facilitate coupled electron and proton movement. Metalloenzymes that accomplish some of the most challenging natural chemical reactions, such as the reduction of oxygen to water or of sulfite to hydrogen sulfide in a continuous process, require more than one metal ion as a combination of different elements or as two or more unique cofactors that contain the same metallic element; such enzymes are said to possess heteronuclear metal centers. In order to understand metalloenzymes and to translate that information into catalysts for biotechnological applications, scientists and engineers have designed artificial metalloenzymes as both structural and functional mimics of native enzymes. However, it is challenging to design artificial enzymes with heteronuclear centers because they tend to be structurally and functionally complex. Decades of research has cemented the understanding that biomimicry of the primary coordination shell around active metal ions is rarely sufficient to reproduce the fine control and stability of natural enzyme metal centers; secondary effects induced by the protein environment are required. A complementary approach to synthetic biomimicry and top-down mutation of native enzymes is biosynthetic modeling. By beginning with stable, natural enzymes that are small, but which share some crucial features with more complex metalloenzymes of interest, there has been significant success in building protein-derived interactions that are necessary and sufficient to engineer the activity and stability of natural enzyme catalysts. A prime example of heteronuclear metalloenzymes is sulfite reductase (SiR), which is an essential enzyme in sulfur assimilation and energy production pathways in bacteria and plants that reduces sulfite (SO32-) to hydrogen sulfide (HS-) at a single heteronuclear metal active center. SiR active sites comprise either a heme cofactor (siroheme) covalently linked to an iron-sulfur cluster ([4Fe-4S]) through a shared Cys ligand or a heme-copper center with linearly coordinated Cu(I) situated ~4 Å above the heme Fe. Both cofactors are biologically unique, reserved only for the six-electron process of sulfite reduction (and closely related nitrite reduction). Despite decades of research into the nature of the siroheme-[4Fe-4S] cofactor, it remains largely a mystery why such a complex cofactor is necessary for sulfite reduction and precisely how its structure and composition are related to efficient catalysis. In this dissertation, I describe the creation of a new structural and functional biosynthetic model of SiR by creating a designed heteronuclear heme-[4Fe-4S] cofactor in cytochrome c peroxidase (CcP). The model (SiRCcP) exhibits spectroscopic and ligand-binding properties of the native enzyme, and sulfite reduction activity was improved—through rational tuning of the secondary sphere interactions around the [4Fe-4S] and the substrate-binding sites—to be close to that of a native enzyme. SiRCcP represents the most complex synthetic metalloenzyme to-date, and the design process provides new insight into the boundaries of biosynthetic engineering. I also describe the design and characterization of a heme-Cu SiR biosynthetic model in the same CcP scaffold (CuICcP) for direct comparison of the mechanisms and structures of these two evolutionarily distinct enzymes. The structure and metal-binding properties of CuICcP are described, as is a relationship to the catalytic properties of heme-copper oxidase, which shares key active site structures with heme-Cu SiR. Additionally, I will describe the creation of the first binuclear Cu binding site with purple copper center properties in a natural protein that is not based on the cupredoxin fold. Together, these studies are explorations into the plasticity of enzyme active sites and their ability to meet design goals that diverge substantially from native structures and represent an expansion of the limits of biomimicry through protein engineering.","Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2020-12-01","The student, Evan Mirts, accepted the attached license on 2018-12-03 at 14:59.","The student, Evan Mirts, submitted this Dissertation for approval on 2018-12-03 at 15:24.","This Dissertation was approved for publication on 2018-12-04 at 16:12.","DSpace SAF Submission Ingestion Package generated from Vireo submission #13179 on 2019-02-07 at 14:18:48","Embargo set by: Seth Robbins for item 109853 Lift date: 2021-02-07T20:44:35Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","U of I Only Restriction Lifted for Item 109853 on 2021-02-08T10:15:11Z."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Complex, non-native heteronuclear metal centers designed in cytochrome c peroxidase: Expanding the limits of biosynthetic modeling"]}]}],"canonical_facts":{"dc:contributor":["Lu, Yi","Crofts, Antony R.","Gennis, Robert B.","Fout, Alison R."],"dc:creator":["Mirts, Evan N."],"dc:date":["2019-02-07T20:44:07Z","2021-02-08T10:15:11Z","2018-12-04","2018-12"],"dc:description":["Made available in DSpace on 2019-02-07T20:44:07Z (GMT). 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Metalloenzymes may contain single metal ions, such as iron or copper, bound to the protein directly or through an organic ligand that chelates the metal, such as porphyrins (heme). Transition metals are especially useful catalytic centers because they can access multiple oxidation states with redox potentials that are tuned by the organic ligand or protein environment to facilitate coupled electron and proton movement. Metalloenzymes that accomplish some of the most challenging natural chemical reactions, such as the reduction of oxygen to water or of sulfite to hydrogen sulfide in a continuous process, require more than one metal ion as a combination of different elements or as two or more unique cofactors that contain the same metallic element; such enzymes are said to possess heteronuclear metal centers. In order to understand metalloenzymes and to translate that information into catalysts for biotechnological applications, scientists and engineers have designed artificial metalloenzymes as both structural and functional mimics of native enzymes. However, it is challenging to design artificial enzymes with heteronuclear centers because they tend to be structurally and functionally complex. Decades of research has cemented the understanding that biomimicry of the primary coordination shell around active metal ions is rarely sufficient to reproduce the fine control and stability of natural enzyme metal centers; secondary effects induced by the protein environment are required. A complementary approach to synthetic biomimicry and top-down mutation of native enzymes is biosynthetic modeling. By beginning with stable, natural enzymes that are small, but which share some crucial features with more complex metalloenzymes of interest, there has been significant success in building protein-derived interactions that are necessary and sufficient to engineer the activity and stability of natural enzyme catalysts. A prime example of heteronuclear metalloenzymes is sulfite reductase (SiR), which is an essential enzyme in sulfur assimilation and energy production pathways in bacteria and plants that reduces sulfite (SO32-) to hydrogen sulfide (HS-) at a single heteronuclear metal active center. SiR active sites comprise either a heme cofactor (siroheme) covalently linked to an iron-sulfur cluster ([4Fe-4S]) through a shared Cys ligand or a heme-copper center with linearly coordinated Cu(I) situated ~4 Å above the heme Fe. Both cofactors are biologically unique, reserved only for the six-electron process of sulfite reduction (and closely related nitrite reduction). Despite decades of research into the nature of the siroheme-[4Fe-4S] cofactor, it remains largely a mystery why such a complex cofactor is necessary for sulfite reduction and precisely how its structure and composition are related to efficient catalysis. In this dissertation, I describe the creation of a new structural and functional biosynthetic model of SiR by creating a designed heteronuclear heme-[4Fe-4S] cofactor in cytochrome c peroxidase (CcP). The model (SiRCcP) exhibits spectroscopic and ligand-binding properties of the native enzyme, and sulfite reduction activity was improved—through rational tuning of the secondary sphere interactions around the [4Fe-4S] and the substrate-binding sites—to be close to that of a native enzyme. SiRCcP represents the most complex synthetic metalloenzyme to-date, and the design process provides new insight into the boundaries of biosynthetic engineering. I also describe the design and characterization of a heme-Cu SiR biosynthetic model in the same CcP scaffold (CuICcP) for direct comparison of the mechanisms and structures of these two evolutionarily distinct enzymes. The structure and metal-binding properties of CuICcP are described, as is a relationship to the catalytic properties of heme-copper oxidase, which shares key active site structures with heme-Cu SiR. Additionally, I will describe the creation of the first binuclear Cu binding site with purple copper center properties in a natural protein that is not based on the cupredoxin fold. Together, these studies are explorations into the plasticity of enzyme active sites and their ability to meet design goals that diverge substantially from native structures and represent an expansion of the limits of biomimicry through protein engineering.","Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2020-12-01","The student, Evan Mirts, accepted the attached license on 2018-12-03 at 14:59.","The student, Evan Mirts, submitted this Dissertation for approval on 2018-12-03 at 15:24.","This Dissertation was approved for publication on 2018-12-04 at 16:12.","DSpace SAF Submission Ingestion Package generated from Vireo submission #13179 on 2019-02-07 at 14:18:48","Embargo set by: Seth Robbins for item 109853 Lift date: 2021-02-07T20:44:35Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","U of I Only Restriction Lifted for Item 109853 on 2021-02-08T10:15:11Z."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/2142/102827"],"dc:language":["en"],"dc:rights":["Copyright 2018 Evan Neal Mirts"],"dc:subject":["protein, biosynthetic, modeling, rational design, metalloprotein, metalloenzyme, heteronuclear, sulfite reductase, sir, cytochrome c peroxidase, peroxidase, ccp, CuA, SiRA, MccA, heme, copper, siroheme"],"dc:title":["Complex, non-native heteronuclear metal centers designed in cytochrome c peroxidase: Expanding the limits of biosynthetic modeling"],"dc:type":["text"],"thesis:degree_discipline":["Biophysics & Computnl Biology"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:42Z"}