Mechanism of Radical Initiation in the Radical SAM Enzyme Superfamily
Radical S -adenosylmethionine (SAM) enzymes use a site-differentiated [4Fe-4S] cluster and SAM to initiate radical reactions through liberation of the 5′-deoxyadenosyl (5′-dAdo*) radical. They form the largest enzyme superfamily, with more than 700,000 unique sequences currently, and their numbers c...
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| Veröffentlicht in: | Annual review of biochemistry 2023-06, Vol.92 (1), p.333-349 |
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| creator | Hoffman, Brian M Broderick, William E Broderick, Joan B |
| description | Radical
S
-adenosylmethionine (SAM) enzymes use a site-differentiated [4Fe-4S] cluster and SAM to initiate radical reactions through liberation of the 5′-deoxyadenosyl (5′-dAdo*) radical. They form the largest enzyme superfamily, with more than 700,000 unique sequences currently, and their numbers continue to grow as a result of ongoing bioinformatics efforts. The range of extremely diverse, highly regio- and stereo-specific reactions known to be catalyzed by radical SAM superfamily members is remarkable. The common mechanism of radical initiation in the radical SAM superfamily is the focus of this review. Most surprising is the presence of an organometallic intermediate, Ω, exhibiting an Fe-C5′-adenosyl bond. Regioselective reductive cleavage of the SAM S-C5′ bond produces 5′-dAdo* to form Ω, with the regioselectivity originating in the Jahn-Teller effect. Ω liberates the free 5′-dAdo* as the catalytically active intermediate through homolysis of the Fe-C5′ bond, in analogy to Co-C5′ bond homolysis in B
12
, which was once viewed as biology's choice of radical generator. |
| doi_str_mv | 10.1146/annurev-biochem-052621-090638 |
| format | Article |
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S
-adenosylmethionine (SAM) enzymes use a site-differentiated [4Fe-4S] cluster and SAM to initiate radical reactions through liberation of the 5′-deoxyadenosyl (5′-dAdo*) radical. They form the largest enzyme superfamily, with more than 700,000 unique sequences currently, and their numbers continue to grow as a result of ongoing bioinformatics efforts. The range of extremely diverse, highly regio- and stereo-specific reactions known to be catalyzed by radical SAM superfamily members is remarkable. The common mechanism of radical initiation in the radical SAM superfamily is the focus of this review. Most surprising is the presence of an organometallic intermediate, Ω, exhibiting an Fe-C5′-adenosyl bond. Regioselective reductive cleavage of the SAM S-C5′ bond produces 5′-dAdo* to form Ω, with the regioselectivity originating in the Jahn-Teller effect. Ω liberates the free 5′-dAdo* as the catalytically active intermediate through homolysis of the Fe-C5′ bond, in analogy to Co-C5′ bond homolysis in B
12
, which was once viewed as biology's choice of radical generator.</description><identifier>ISSN: 0066-4154</identifier><identifier>ISSN: 1545-4509</identifier><identifier>EISSN: 1545-4509</identifier><identifier>DOI: 10.1146/annurev-biochem-052621-090638</identifier><identifier>PMID: 37018846</identifier><language>eng</language><publisher>United States: Annual Reviews</publisher><subject>5'-deoxyadenosyl radical ; Adenosylmethionine ; BASIC BIOLOGICAL SCIENCES ; Biochemistry & Molecular Biology ; Bioinformatics ; Chemical reactions ; Enzymes ; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY ; Iron-Sulfur Proteins - chemistry ; Iron-Sulfur Proteins - genetics ; Jahn-Teller effect ; organometallic ; radical SAM ; Regioselectivity ; S-Adenosylmethionine ; S-Adenosylmethionine - chemistry</subject><ispartof>Annual review of biochemistry, 2023-06, Vol.92 (1), p.333-349</ispartof><rights>Copyright Annual Reviews, Inc. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a550t-f2b76bd48a36e1892cca1c05ce7c977e19f95feee036fad78aaf9708857d1a913</citedby><cites>FETCH-LOGICAL-a550t-f2b76bd48a36e1892cca1c05ce7c977e19f95feee036fad78aaf9708857d1a913</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.annualreviews.org/content/journals/10.1146/annurev-biochem-052621-090638?crawler=true&mimetype=application/pdf$$EPDF$$P50$$Gannualreviews$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.annualreviews.org/content/journals/10.1146/annurev-biochem-052621-090638$$EHTML$$P50$$Gannualreviews$$Hfree_for_read</linktohtml><link.rule.ids>70,230,314,780,784,885,4182,27924,27925,78254,78255</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37018846$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/2419699$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Hoffman, Brian M</creatorcontrib><creatorcontrib>Broderick, William E</creatorcontrib><creatorcontrib>Broderick, Joan B</creatorcontrib><creatorcontrib>Montana State Univ., Bozeman, MT (United States)</creatorcontrib><title>Mechanism of Radical Initiation in the Radical SAM Enzyme Superfamily</title><title>Annual review of biochemistry</title><addtitle>Annu Rev Biochem</addtitle><description>Radical
S
-adenosylmethionine (SAM) enzymes use a site-differentiated [4Fe-4S] cluster and SAM to initiate radical reactions through liberation of the 5′-deoxyadenosyl (5′-dAdo*) radical. They form the largest enzyme superfamily, with more than 700,000 unique sequences currently, and their numbers continue to grow as a result of ongoing bioinformatics efforts. The range of extremely diverse, highly regio- and stereo-specific reactions known to be catalyzed by radical SAM superfamily members is remarkable. The common mechanism of radical initiation in the radical SAM superfamily is the focus of this review. Most surprising is the presence of an organometallic intermediate, Ω, exhibiting an Fe-C5′-adenosyl bond. Regioselective reductive cleavage of the SAM S-C5′ bond produces 5′-dAdo* to form Ω, with the regioselectivity originating in the Jahn-Teller effect. Ω liberates the free 5′-dAdo* as the catalytically active intermediate through homolysis of the Fe-C5′ bond, in analogy to Co-C5′ bond homolysis in B
12
, which was once viewed as biology's choice of radical generator.</description><subject>5'-deoxyadenosyl radical</subject><subject>Adenosylmethionine</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Biochemistry & Molecular Biology</subject><subject>Bioinformatics</subject><subject>Chemical reactions</subject><subject>Enzymes</subject><subject>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</subject><subject>Iron-Sulfur Proteins - chemistry</subject><subject>Iron-Sulfur Proteins - genetics</subject><subject>Jahn-Teller effect</subject><subject>organometallic</subject><subject>radical SAM</subject><subject>Regioselectivity</subject><subject>S-Adenosylmethionine</subject><subject>S-Adenosylmethionine - chemistry</subject><issn>0066-4154</issn><issn>1545-4509</issn><issn>1545-4509</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVkU1v1DAQhi0EokvhL6AIhMQlYCfxxxwQKtUWKrVConC2Zr0T1lViL3FStPz6epVlBdw4WfK884zHD2OvBH8jRKPeYgjTQHflyke3ob7kslKVKDlwVZsHbCFkI8tGcnjIFpwrVTb55oQ9SemWc15DUz1mJ7XmwphGLdjymtwGg099EdviC669w664DH70OPoYCh-KcUPHys3ZdbEMv3Y9FTfTloYWe9_tnrJHLXaJnh3OU_btYvn1_FN59fnj5fnZVYlS8rFsq5VWq3VjsFYkDFTOoXBcOtIOtCYBLciWiHitWlxrg9iC5sZIvRYIoj5l72fudlr1tHYUxgE7ux18j8PORvT270rwG_s93lnBtQSoTCa8mAkxjd4m58e8v4shkBtt1QhQADn0-jBmiD8mSqPtfXLUdRgoTslWGnR2IUHm6Mt_ordxGkL-BJunAQgFZg98N6fcEFMaqD0-WXC712oPWu1Bq5212llr7n_-597H7t8ec-DDHNhzsMskTz_Tf065BwtIuhw</recordid><startdate>20230620</startdate><enddate>20230620</enddate><creator>Hoffman, Brian M</creator><creator>Broderick, William E</creator><creator>Broderick, Joan B</creator><general>Annual Reviews</general><general>Annual Reviews, Inc</general><scope>ZYWBE</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20230620</creationdate><title>Mechanism of Radical Initiation in the Radical SAM Enzyme Superfamily</title><author>Hoffman, Brian M ; Broderick, William E ; Broderick, Joan B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a550t-f2b76bd48a36e1892cca1c05ce7c977e19f95feee036fad78aaf9708857d1a913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>5'-deoxyadenosyl radical</topic><topic>Adenosylmethionine</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Biochemistry & Molecular Biology</topic><topic>Bioinformatics</topic><topic>Chemical reactions</topic><topic>Enzymes</topic><topic>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</topic><topic>Iron-Sulfur Proteins - chemistry</topic><topic>Iron-Sulfur Proteins - genetics</topic><topic>Jahn-Teller effect</topic><topic>organometallic</topic><topic>radical SAM</topic><topic>Regioselectivity</topic><topic>S-Adenosylmethionine</topic><topic>S-Adenosylmethionine - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hoffman, Brian M</creatorcontrib><creatorcontrib>Broderick, William E</creatorcontrib><creatorcontrib>Broderick, Joan B</creatorcontrib><creatorcontrib>Montana State Univ., Bozeman, MT (United States)</creatorcontrib><collection>Annual Reviews Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV - Hybrid</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Annual review of biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hoffman, Brian M</au><au>Broderick, William E</au><au>Broderick, Joan B</au><aucorp>Montana State Univ., Bozeman, MT (United States)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism of Radical Initiation in the Radical SAM Enzyme Superfamily</atitle><jtitle>Annual review of biochemistry</jtitle><addtitle>Annu Rev Biochem</addtitle><date>2023-06-20</date><risdate>2023</risdate><volume>92</volume><issue>1</issue><spage>333</spage><epage>349</epage><pages>333-349</pages><issn>0066-4154</issn><issn>1545-4509</issn><eissn>1545-4509</eissn><abstract>Radical
S
-adenosylmethionine (SAM) enzymes use a site-differentiated [4Fe-4S] cluster and SAM to initiate radical reactions through liberation of the 5′-deoxyadenosyl (5′-dAdo*) radical. They form the largest enzyme superfamily, with more than 700,000 unique sequences currently, and their numbers continue to grow as a result of ongoing bioinformatics efforts. The range of extremely diverse, highly regio- and stereo-specific reactions known to be catalyzed by radical SAM superfamily members is remarkable. The common mechanism of radical initiation in the radical SAM superfamily is the focus of this review. Most surprising is the presence of an organometallic intermediate, Ω, exhibiting an Fe-C5′-adenosyl bond. Regioselective reductive cleavage of the SAM S-C5′ bond produces 5′-dAdo* to form Ω, with the regioselectivity originating in the Jahn-Teller effect. Ω liberates the free 5′-dAdo* as the catalytically active intermediate through homolysis of the Fe-C5′ bond, in analogy to Co-C5′ bond homolysis in B
12
, which was once viewed as biology's choice of radical generator.</abstract><cop>United States</cop><pub>Annual Reviews</pub><pmid>37018846</pmid><doi>10.1146/annurev-biochem-052621-090638</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 5'-deoxyadenosyl radical Adenosylmethionine BASIC BIOLOGICAL SCIENCES Biochemistry & Molecular Biology Bioinformatics Chemical reactions Enzymes INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY Iron-Sulfur Proteins - chemistry Iron-Sulfur Proteins - genetics Jahn-Teller effect organometallic radical SAM Regioselectivity S-Adenosylmethionine S-Adenosylmethionine - chemistry |
| title | Mechanism of Radical Initiation in the Radical SAM Enzyme Superfamily |
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