Structural basis of autoregulation of phenylalanine hydroxylase
Phenylalanine hydroxylase converts phenylalanine to tyrosine, a rate-limiting step in phenylalanine catabolism and protein and neurotransmitter biosynthesis. It is tightly regulated by the substrates phenylalanine and tetrahydrobiopterin and by phosphorylation. We present the crystal structures of d...
Gespeichert in:
| Veröffentlicht in: | Nature Structural Biology 1999-05, Vol.6 (5), p.442-448 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 448 |
|---|---|
| container_issue | 5 |
| container_start_page | 442 |
| container_title | Nature Structural Biology |
| container_volume | 6 |
| creator | Kobe, Bostjan Jennings, Ian G House, Colin M Michell, Belinda J Goodwill, Kenneth E Santarsiero, Bernard D Stevens, Raymond C Cotton, Richard G. H Kemp, Bruce E |
| description | Phenylalanine hydroxylase converts phenylalanine to tyrosine, a rate-limiting step in phenylalanine catabolism and protein and neurotransmitter biosynthesis. It is tightly regulated by the substrates phenylalanine and tetrahydrobiopterin and by phosphorylation. We present the crystal structures of dephosphorylated and phosphorylated forms of a dimeric enzyme with catalytic and regulatory properties of the wild-type protein. The structures reveal a catalytic domain flexibly linked to a regulatory domain. The latter consists of an N-terminal autoregulatory sequence (containing Ser 16, which is the site of phosphorylation) that extends over the active site pocket, and an α-β sandwich core that is, unexpectedly, structurally related to both pterin dehydratase and the regulatory domains of metabolic enzymes. Phosphorylation has no major structural effects in the absence of phenylalanine, suggesting that phenylalanine and phosphorylation act in concert to activate the enzyme through a combination of intrasteric and possibly allosteric mechanisms. |
| doi_str_mv | 10.1038/8247 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_69755480</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>69755480</sourcerecordid><originalsourceid>FETCH-LOGICAL-c364t-fa1afed3af73595d6a8acf2c5d7ff86fdb0e1735dc602e761149c0de87d13adf3</originalsourceid><addsrcrecordid>eNo9kE9LAzEQxYMotrZ-BakHva0mm2ySPYkU_0HBgwreltnNpF3ZZmuyAfvtTWn1NMy83zxmHiFTRm8Y5fpW50IdkXHOOcu4LD6PyZhRlWeaSz0iZyF8UcqEoOUpGaUFzrRiY3L3NvjYDNFDN6shtGHW2xnEofe4jB0Mbe92k80K3baDDlzrcLbaGt__pD7glJxY6AKeH-qEfDw-vM-fs8Xr08v8fpE1XIohs8DAouFgFS_KwkjQ0Ni8KYyyVktraoosSaaRNEclGRNlQw1qZRgHY_mEXO99N77_jhiGat2GBrt0EfYxVLJURSE0TeDFAYz1Gk218e0a_Lb6ezkBV3sgJMkt0VdfffQuHZ-YHaarXZSJu9xzDlI8-G_kQk2LsqyEyPkvTl9vlQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>69755480</pqid></control><display><type>article</type><title>Structural basis of autoregulation of phenylalanine hydroxylase</title><source>MEDLINE</source><source>Nature</source><source>Alma/SFX Local Collection</source><creator>Kobe, Bostjan ; Jennings, Ian G ; House, Colin M ; Michell, Belinda J ; Goodwill, Kenneth E ; Santarsiero, Bernard D ; Stevens, Raymond C ; Cotton, Richard G. H ; Kemp, Bruce E</creator><creatorcontrib>Kobe, Bostjan ; Jennings, Ian G ; House, Colin M ; Michell, Belinda J ; Goodwill, Kenneth E ; Santarsiero, Bernard D ; Stevens, Raymond C ; Cotton, Richard G. H ; Kemp, Bruce E</creatorcontrib><description>Phenylalanine hydroxylase converts phenylalanine to tyrosine, a rate-limiting step in phenylalanine catabolism and protein and neurotransmitter biosynthesis. It is tightly regulated by the substrates phenylalanine and tetrahydrobiopterin and by phosphorylation. We present the crystal structures of dephosphorylated and phosphorylated forms of a dimeric enzyme with catalytic and regulatory properties of the wild-type protein. The structures reveal a catalytic domain flexibly linked to a regulatory domain. The latter consists of an N-terminal autoregulatory sequence (containing Ser 16, which is the site of phosphorylation) that extends over the active site pocket, and an α-β sandwich core that is, unexpectedly, structurally related to both pterin dehydratase and the regulatory domains of metabolic enzymes. Phosphorylation has no major structural effects in the absence of phenylalanine, suggesting that phenylalanine and phosphorylation act in concert to activate the enzyme through a combination of intrasteric and possibly allosteric mechanisms.</description><identifier>ISSN: 1072-8368</identifier><identifier>EISSN: 2331-365X</identifier><identifier>EISSN: 1545-9985</identifier><identifier>DOI: 10.1038/8247</identifier><identifier>PMID: 10331871</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Allosteric Regulation - drug effects ; Amino Acid Sequence ; Animals ; Binding Sites - genetics ; Biochemistry ; Biological Microscopy ; Biomedical and Life Sciences ; Catalytic Domain - genetics ; Crystallization ; Crystallography, X-Ray ; Dimerization ; Evolution, Molecular ; Humans ; letter ; Life Sciences ; Membrane Biology ; Mixed Function Oxygenases - chemistry ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Peptide Fragments - chemistry ; Peptide Fragments - genetics ; Peptide Fragments - metabolism ; Phenylalanine - metabolism ; Phenylalanine - pharmacology ; Phenylalanine Hydroxylase - chemistry ; Phenylalanine Hydroxylase - genetics ; Phenylalanine Hydroxylase - metabolism ; Phenylketonurias - enzymology ; Phenylketonurias - genetics ; Phosphorylation ; Protein Conformation ; Protein Structure ; Rats ; Sequence Homology, Amino Acid ; Space life sciences</subject><ispartof>Nature Structural Biology, 1999-05, Vol.6 (5), p.442-448</ispartof><rights>Nature America Inc. 1999</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c364t-fa1afed3af73595d6a8acf2c5d7ff86fdb0e1735dc602e761149c0de87d13adf3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2727,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10331871$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kobe, Bostjan</creatorcontrib><creatorcontrib>Jennings, Ian G</creatorcontrib><creatorcontrib>House, Colin M</creatorcontrib><creatorcontrib>Michell, Belinda J</creatorcontrib><creatorcontrib>Goodwill, Kenneth E</creatorcontrib><creatorcontrib>Santarsiero, Bernard D</creatorcontrib><creatorcontrib>Stevens, Raymond C</creatorcontrib><creatorcontrib>Cotton, Richard G. H</creatorcontrib><creatorcontrib>Kemp, Bruce E</creatorcontrib><title>Structural basis of autoregulation of phenylalanine hydroxylase</title><title>Nature Structural Biology</title><addtitle>Nat Struct Mol Biol</addtitle><addtitle>Nat Struct Biol</addtitle><description>Phenylalanine hydroxylase converts phenylalanine to tyrosine, a rate-limiting step in phenylalanine catabolism and protein and neurotransmitter biosynthesis. It is tightly regulated by the substrates phenylalanine and tetrahydrobiopterin and by phosphorylation. We present the crystal structures of dephosphorylated and phosphorylated forms of a dimeric enzyme with catalytic and regulatory properties of the wild-type protein. The structures reveal a catalytic domain flexibly linked to a regulatory domain. The latter consists of an N-terminal autoregulatory sequence (containing Ser 16, which is the site of phosphorylation) that extends over the active site pocket, and an α-β sandwich core that is, unexpectedly, structurally related to both pterin dehydratase and the regulatory domains of metabolic enzymes. Phosphorylation has no major structural effects in the absence of phenylalanine, suggesting that phenylalanine and phosphorylation act in concert to activate the enzyme through a combination of intrasteric and possibly allosteric mechanisms.</description><subject>Allosteric Regulation - drug effects</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Binding Sites - genetics</subject><subject>Biochemistry</subject><subject>Biological Microscopy</subject><subject>Biomedical and Life Sciences</subject><subject>Catalytic Domain - genetics</subject><subject>Crystallization</subject><subject>Crystallography, X-Ray</subject><subject>Dimerization</subject><subject>Evolution, Molecular</subject><subject>Humans</subject><subject>letter</subject><subject>Life Sciences</subject><subject>Membrane Biology</subject><subject>Mixed Function Oxygenases - chemistry</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - genetics</subject><subject>Peptide Fragments - metabolism</subject><subject>Phenylalanine - metabolism</subject><subject>Phenylalanine - pharmacology</subject><subject>Phenylalanine Hydroxylase - chemistry</subject><subject>Phenylalanine Hydroxylase - genetics</subject><subject>Phenylalanine Hydroxylase - metabolism</subject><subject>Phenylketonurias - enzymology</subject><subject>Phenylketonurias - genetics</subject><subject>Phosphorylation</subject><subject>Protein Conformation</subject><subject>Protein Structure</subject><subject>Rats</subject><subject>Sequence Homology, Amino Acid</subject><subject>Space life sciences</subject><issn>1072-8368</issn><issn>2331-365X</issn><issn>1545-9985</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE9LAzEQxYMotrZ-BakHva0mm2ySPYkU_0HBgwreltnNpF3ZZmuyAfvtTWn1NMy83zxmHiFTRm8Y5fpW50IdkXHOOcu4LD6PyZhRlWeaSz0iZyF8UcqEoOUpGaUFzrRiY3L3NvjYDNFDN6shtGHW2xnEofe4jB0Mbe92k80K3baDDlzrcLbaGt__pD7glJxY6AKeH-qEfDw-vM-fs8Xr08v8fpE1XIohs8DAouFgFS_KwkjQ0Ni8KYyyVktraoosSaaRNEclGRNlQw1qZRgHY_mEXO99N77_jhiGat2GBrt0EfYxVLJURSE0TeDFAYz1Gk218e0a_Lb6ezkBV3sgJMkt0VdfffQuHZ-YHaarXZSJu9xzDlI8-G_kQk2LsqyEyPkvTl9vlQ</recordid><startdate>19990501</startdate><enddate>19990501</enddate><creator>Kobe, Bostjan</creator><creator>Jennings, Ian G</creator><creator>House, Colin M</creator><creator>Michell, Belinda J</creator><creator>Goodwill, Kenneth E</creator><creator>Santarsiero, Bernard D</creator><creator>Stevens, Raymond C</creator><creator>Cotton, Richard G. H</creator><creator>Kemp, Bruce E</creator><general>Nature Publishing Group US</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19990501</creationdate><title>Structural basis of autoregulation of phenylalanine hydroxylase</title><author>Kobe, Bostjan ; Jennings, Ian G ; House, Colin M ; Michell, Belinda J ; Goodwill, Kenneth E ; Santarsiero, Bernard D ; Stevens, Raymond C ; Cotton, Richard G. H ; Kemp, Bruce E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c364t-fa1afed3af73595d6a8acf2c5d7ff86fdb0e1735dc602e761149c0de87d13adf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Allosteric Regulation - drug effects</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Binding Sites - genetics</topic><topic>Biochemistry</topic><topic>Biological Microscopy</topic><topic>Biomedical and Life Sciences</topic><topic>Catalytic Domain - genetics</topic><topic>Crystallization</topic><topic>Crystallography, X-Ray</topic><topic>Dimerization</topic><topic>Evolution, Molecular</topic><topic>Humans</topic><topic>letter</topic><topic>Life Sciences</topic><topic>Membrane Biology</topic><topic>Mixed Function Oxygenases - chemistry</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptide Fragments - genetics</topic><topic>Peptide Fragments - metabolism</topic><topic>Phenylalanine - metabolism</topic><topic>Phenylalanine - pharmacology</topic><topic>Phenylalanine Hydroxylase - chemistry</topic><topic>Phenylalanine Hydroxylase - genetics</topic><topic>Phenylalanine Hydroxylase - metabolism</topic><topic>Phenylketonurias - enzymology</topic><topic>Phenylketonurias - genetics</topic><topic>Phosphorylation</topic><topic>Protein Conformation</topic><topic>Protein Structure</topic><topic>Rats</topic><topic>Sequence Homology, Amino Acid</topic><topic>Space life sciences</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kobe, Bostjan</creatorcontrib><creatorcontrib>Jennings, Ian G</creatorcontrib><creatorcontrib>House, Colin M</creatorcontrib><creatorcontrib>Michell, Belinda J</creatorcontrib><creatorcontrib>Goodwill, Kenneth E</creatorcontrib><creatorcontrib>Santarsiero, Bernard D</creatorcontrib><creatorcontrib>Stevens, Raymond C</creatorcontrib><creatorcontrib>Cotton, Richard G. H</creatorcontrib><creatorcontrib>Kemp, Bruce E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Nature Structural Biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kobe, Bostjan</au><au>Jennings, Ian G</au><au>House, Colin M</au><au>Michell, Belinda J</au><au>Goodwill, Kenneth E</au><au>Santarsiero, Bernard D</au><au>Stevens, Raymond C</au><au>Cotton, Richard G. H</au><au>Kemp, Bruce E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural basis of autoregulation of phenylalanine hydroxylase</atitle><jtitle>Nature Structural Biology</jtitle><stitle>Nat Struct Mol Biol</stitle><addtitle>Nat Struct Biol</addtitle><date>1999-05-01</date><risdate>1999</risdate><volume>6</volume><issue>5</issue><spage>442</spage><epage>448</epage><pages>442-448</pages><issn>1072-8368</issn><eissn>2331-365X</eissn><eissn>1545-9985</eissn><abstract>Phenylalanine hydroxylase converts phenylalanine to tyrosine, a rate-limiting step in phenylalanine catabolism and protein and neurotransmitter biosynthesis. It is tightly regulated by the substrates phenylalanine and tetrahydrobiopterin and by phosphorylation. We present the crystal structures of dephosphorylated and phosphorylated forms of a dimeric enzyme with catalytic and regulatory properties of the wild-type protein. The structures reveal a catalytic domain flexibly linked to a regulatory domain. The latter consists of an N-terminal autoregulatory sequence (containing Ser 16, which is the site of phosphorylation) that extends over the active site pocket, and an α-β sandwich core that is, unexpectedly, structurally related to both pterin dehydratase and the regulatory domains of metabolic enzymes. Phosphorylation has no major structural effects in the absence of phenylalanine, suggesting that phenylalanine and phosphorylation act in concert to activate the enzyme through a combination of intrasteric and possibly allosteric mechanisms.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>10331871</pmid><doi>10.1038/8247</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1072-8368 |
| ispartof | Nature Structural Biology, 1999-05, Vol.6 (5), p.442-448 |
| issn | 1072-8368 2331-365X 1545-9985 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_69755480 |
| source | MEDLINE; Nature; Alma/SFX Local Collection |
| subjects | Allosteric Regulation - drug effects Amino Acid Sequence Animals Binding Sites - genetics Biochemistry Biological Microscopy Biomedical and Life Sciences Catalytic Domain - genetics Crystallization Crystallography, X-Ray Dimerization Evolution, Molecular Humans letter Life Sciences Membrane Biology Mixed Function Oxygenases - chemistry Models, Molecular Molecular Sequence Data Mutation Peptide Fragments - chemistry Peptide Fragments - genetics Peptide Fragments - metabolism Phenylalanine - metabolism Phenylalanine - pharmacology Phenylalanine Hydroxylase - chemistry Phenylalanine Hydroxylase - genetics Phenylalanine Hydroxylase - metabolism Phenylketonurias - enzymology Phenylketonurias - genetics Phosphorylation Protein Conformation Protein Structure Rats Sequence Homology, Amino Acid Space life sciences |
| title | Structural basis of autoregulation of phenylalanine hydroxylase |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-28T07%3A52%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Structural%20basis%20of%20autoregulation%20of%20phenylalanine%20hydroxylase&rft.jtitle=Nature%20Structural%20Biology&rft.au=Kobe,%20Bostjan&rft.date=1999-05-01&rft.volume=6&rft.issue=5&rft.spage=442&rft.epage=448&rft.pages=442-448&rft.issn=1072-8368&rft.eissn=2331-365X&rft_id=info:doi/10.1038/8247&rft_dat=%3Cproquest_pubme%3E69755480%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=69755480&rft_id=info:pmid/10331871&rfr_iscdi=true |