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To answer this question, we report herein the design of either a CuB or a CuSiR site in a single protein, soybean ascorbate peroxidase (APX), as a scaffold to mimic those in HCO and SiR-A, respectively. By eliminating confounding factors from different native scaffolds, we isolate the intrinsic roles of copper coordination environments and a conserved Tyr in catalyzing fundamentally different reactions, offering unprecedented clarity on how these centers govern these reactions. Our results reveal that both CuB and CuSiR sites can support ORR, but only CuSiR promotes SRR, underscoring the greater challenge of 6e\u2013 \/7H+ transfer versus 4e\u2013 \/4H+. Surprisingly, introducing a Tyr near the CuB site not only enhances ORR but also confers robust SRR activity, surpassing even CuSiR under identical conditions. This finding changed the view that copper coordination alone dictates catalytic specificity and highlights the dominant role of Tyr\u2013Cu synergy in enabling multielectron redox chemistry. These insights provide a new framework for understanding evolutionary design principles and for creating bioinspired catalysts for selective O2 and SO32\u2013 reductions.<\/jats:p>","DOI":"10.1021\/jacs.6c00223","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T16:02:32Z","timestamp":1786377752000},"page":"34094-34101","source":"Crossref","is-referenced-by-count":0,"title":["Direct Comparison of\nCuB and CuSiR Sites in a Single Designed Protein\nScaffold Reveals a Central Role\nfor Tyrosine in Oxygen and Sulfite Reduction"],"prefix":"10.1021","volume":"148","author":[{"given":"Aaron P.","family":"Ledray","sequence":"first","affiliation":[{"name":"University of Texas at Austin , , , ,","place":["Austin, Texas, United States, 78712"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barshali","family":"Ghosh","sequence":"additional","affiliation":[{"name":"University of Texas at Austin , , , ,","place":["Austin, Texas, United States, 78712"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5191-1512","authenticated-orcid":true,"given":"Hirbod","family":"Heidari","sequence":"additional","affiliation":[{"name":"University of Texas at Austin , , , ,","place":["Austin, Texas, United States, 78712"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1221-6709","authenticated-orcid":true,"given":"Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"University of Texas at Austin , , , ,","place":["Austin, Texas, United States, 78712"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"issue":"7","key":"2026081910205788800_cit1","doi-asserted-by":"publisher","first-page":"2889","DOI":"10.1021\/cr950051s","article-title":"Heme\/Copper Terminal Oxidases","volume":"96","author":"Ferguson-Miller","year":"1996","journal-title":"Chem. 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Rev."},{"issue":"7","key":"2026081910205788800_cit5","doi-asserted-by":"publisher","first-page":"msac139","DOI":"10.1093\/molbev\/msac139","article-title":"A New Paradigm\nof Multiheme Cytochrome Evolution by Grafting and Pruning Protein\nModules","volume":"39","author":"Soares","year":"2022","journal-title":"Mol. Biol. Evol."},{"issue":"2","key":"2026081910205788800_cit6","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/BF00762225","article-title":"Evolutionary\nAspects of Cytochromec Oxidase","volume":"23","author":"Kadenbach","year":"1991","journal-title":"J. Bioenerg.\nBiomembr."},{"issue":"6","key":"2026081910205788800_cit7","doi-asserted-by":"publisher","first-page":"2543","DOI":"10.1016\/S0006-3495(95)80437-6","article-title":"Understanding the Cytochrome c Oxidase Proton Pump:\nThermodynamics of Redox Linkage","volume":"68","author":"Musser","year":"1995","journal-title":"Biophys. 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Microbiol."},{"issue":"11","key":"2026081910205788800_cit24","doi-asserted-by":"publisher","first-page":"3150","DOI":"10.1111\/j.1462-2920.2008.01733.x","article-title":"Evolution of an\nOctahaem Cytochrome\nc Protein Family That Is Key to Aerobic and Anaerobic Ammonia Oxidation\nby Bacteria","volume":"10","author":"Klotz","year":"2008","journal-title":"Environ. Microbiol."},{"issue":"6","key":"2026081910205788800_cit25","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1111\/j.1365-2958.2011.07906.x","article-title":"The Wolinella Succinogenes Mcc Gene\nCluster Encodes an Unconventional Respiratory Sulphite Reduction System","volume":"82","author":"Kern","year":"2011","journal-title":"Mol. Microbiol."},{"key":"2026081910205788800_cit26","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/B978-0-12-410515-7.00002-0","article-title":"Chapter\nTwo - Microbial Sulfite Respiration","volume-title":"Advances\nin Microbial Physiology","author":"Simon","year":"2013"},{"issue":"47","key":"2026081910205788800_cit27","doi-asserted-by":"publisher","first-page":"16541","DOI":"10.1021\/ja052659g","article-title":"Role of Heme\nTypes in Heme-Copper\nOxidases: Effects of Replacing a Heme b with a Heme o Mimic in an\nEngineered Heme-Copper Center in Myoglobin","volume":"127","author":"Wang","year":"2005","journal-title":"J. Am. Chem. Soc."},{"issue":"4","key":"2026081910205788800_cit28","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1021\/bi0479151","article-title":"Effects of\nMetal Ions in the CuB Center on the Redox Properties of Heme in Heme-Copper\nOxidases: Spectroelectrochemical Studies of an Engineered Heme-Copper\nCenter in Myoglobin","volume":"44","author":"Zhao","year":"2005","journal-title":"Biochemistry"},{"issue":"7","key":"2026081910205788800_cit29","doi-asserted-by":"publisher","first-page":"3629","DOI":"10.1073\/pnas.0737308100","article-title":"The Role of\nCopper and Protons in Heme-Copper Oxidases: Kinetic Study of an Engineered\nHeme-Copper Center in Myoglobin","volume":"100","author":"Sigman","year":"2003","journal-title":"Proc. Natl.\nAcad. Sci. U. S. A."},{"issue":"21","key":"2026081910205788800_cit30","doi-asserted-by":"publisher","first-page":"6766","DOI":"10.1021\/ja058822p","article-title":"Catalytic\nReduction of NO to N2O by a Designed Heme Copper Center in Myoglobin:\nImplications for the Role of Metal Ions","volume":"128","author":"Zhao","year":"2006","journal-title":"J.\nAm. Chem. Soc."},{"issue":"8","key":"2026081910205788800_cit31","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1002\/cbdv.200890134","article-title":"One Heme, Diverse Functions:\nUsing Biosynthetic Myoglobin Models\nto Gain Insights into Heme-Copper Oxidases and Nitric Oxide Reductases","volume":"5","author":"Yeung","year":"2008","journal-title":"Chem. Biodiversity"},{"issue":"18","key":"2026081910205788800_cit32","doi-asserted-by":"publisher","first-page":"4312","DOI":"10.1002\/anie.201108756","article-title":"Significant\nIncrease of Oxidase Activity through the Genetic Incorporation of\na Tyrosine-Histidine Cross-Link in a Myoglobin Model of Heme-Copper\nOxidase","volume":"51","author":"Liu","year":"2012","journal-title":"Angew. Chem., Int. Ed."},{"issue":"5","key":"2026081910205788800_cit33","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1021\/ja907777f","article-title":"Role of\nCopper Ion in Regulating Ligand Binding in a Myoglobin-Based Cytochrome\nC Oxidase Model","volume":"132","author":"Lu","year":"2010","journal-title":"J. Am. Chem. Soc."},{"issue":"4","key":"2026081910205788800_cit34","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1021\/ja4091885","article-title":"Direct EPR\nObservation of a Tyrosyl\nRadical in a Functional Oxidase Model in Myoglobin during Both H2O2\nand O2 Reactions","volume":"136","author":"Yu","year":"2014","journal-title":"J. Am. Chem. Soc."},{"issue":"34","key":"2026081910205788800_cit35","doi-asserted-by":"publisher","first-page":"11882","DOI":"10.1021\/ja5054863","article-title":"Systematic\nTuning of Heme Redox Potentials and Its Effects on O2 Reduction Rates\nin a Designed Oxidase in Myoglobin","volume":"136","author":"Bhagi-Damodaran","year":"2014","journal-title":"J. Am. Chem.\nSoc."},{"issue":"4","key":"2026081910205788800_cit36","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1021\/jacs.5b12004","article-title":"Spectroscopic and Crystallographic Evidence for the Role of a Water-Containing\nH-Bond Network in Oxidase Activity of an Engineered Myoglobin","volume":"138","author":"Petrik","year":"2016","journal-title":"J. Am. Chem. Soc."},{"issue":"7","key":"2026081910205788800_cit37","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1038\/nchem.2489","article-title":"Reversible\nS-Nitrosylation in an\nEngineered Azurin","volume":"8","author":"Tian","year":"2016","journal-title":"Nat. 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Chem."},{"issue":"35","key":"2026081910205788800_cit40","doi-asserted-by":"publisher","first-page":"12209","DOI":"10.1021\/jacs.7b05800","article-title":"Manganese and Cobalt in the Nonheme-Metal-Binding\nSite of a Biosynthetic Model of Heme-Copper Oxidase Superfamily Confer\nOxidase Activity through Redox-Inactive Mechanism","volume":"139","author":"Reed","year":"2017","journal-title":"J. Am. Chem. Soc."},{"issue":"23","key":"2026081910205788800_cit41","doi-asserted-by":"publisher","first-page":"6622","DOI":"10.1002\/anie.201701916","article-title":"Insights Into How Heme\nReduction Potentials Modulate Enzymatic Activities\nof a Myoglobin-Based Functional Oxidase","volume":"56","author":"Bhagi-Damodaran","year":"2017","journal-title":"Angew.\nChem., Int. Ed."},{"issue":"24","key":"2026081910205788800_cit42","doi-asserted-by":"publisher","first-page":"6195","DOI":"10.1073\/pnas.1720298115","article-title":"Heme Redox\nPotentials Hold the Key to Reactivity Differences between\nNitric Oxide Reductase and Heme-Copper Oxidase","volume":"115","author":"Bhagi-Damodaran","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"4","key":"2026081910205788800_cit43","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1021\/acs.biochem.0c00852","article-title":"An Engineered Glutamate\nin Biosynthetic Models of Heme-Copper Oxidases Drives Complete Product\nSelectivity by Tuning the Hydrogen-Bonding Network","volume":"60","author":"Petrik","year":"2021","journal-title":"Biochemistry"},{"issue":"4","key":"2026081910205788800_cit44","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1021\/acs.accounts.9b00011","article-title":"Understanding and Modulating\nMetalloenzymes\nwith Unnatural Amino Acids, Non-Native Metal Ions, and Non-Native\nMetallocofactors","volume":"52","author":"Mirts","year":"2019","journal-title":"Acc. Chem. Res."},{"issue":"2","key":"2026081910205788800_cit45","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1021\/acs.biochem.2c00300","article-title":"Tryptophan Can Promote Oxygen Reduction\nto Water in a Biosynthetic\nModel of Heme Copper Oxidases","volume":"62","author":"Ledray","year":"2023","journal-title":"Biochemistry"},{"issue":"41","key":"2026081910205788800_cit46","doi-asserted-by":"publisher","first-page":"37688","DOI":"10.1021\/jacs.5c12710","article-title":"A Post-Translational\nHistidine-Histidine Cross-Link Enhances Enzymatic\nOxygen Reduction Activity with Greater pH Adaptability","volume":"147","author":"Liu","year":"2025","journal-title":"J. Am. Chem. Soc."},{"key":"2026081910205788800_cit47","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/bs.mie.2025.08.004","article-title":"Design and Preparation\nof Artificial Heme-Copper Enzymes","volume":"720","author":"Heidari","year":"2025","journal-title":"Methods Enzymol."},{"issue":"27","key":"2026081910205788800_cit48","doi-asserted-by":"publisher","first-page":"8152","DOI":"10.1021\/ja012514j","article-title":"Electron-Mediating\nCu(A) Centers in Proteins: A Comparative High Field (1)H ENDOR Study","volume":"124","author":"Epel","year":"2002","journal-title":"J. Am. Chem. Soc."},{"issue":"51","key":"2026081910205788800_cit49","doi-asserted-by":"publisher","first-page":"20778","DOI":"10.1021\/ja205281t","article-title":"Kinetics of\nCopper Incorporation into a Biosynthetic Purple Cu(A) Azurin: Characterization\nof Red, Blue, and a New Intermediate Species","volume":"133","author":"Wilson","year":"2011","journal-title":"J. Am. Chem. 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