Structure of the human beta-ketoacyl [ACP] synthase from the mitochondrial type II fatty acid synthase.

Caspar Elo Christensen; Birthe B Kragelund; Penny von Wettstein-Knowles; Anette Henriksen

doi:10.1110/ps.062473707

Structure of the human beta-ketoacyl [ACP] synthase from the mitochondrial type II fatty acid synthase.

Caspar Elo Christensen, Birthe B Kragelund, Penny von Wettstein-Knowles, Anette Henriksen

Biomolecular Sciences

49 Citationer (Scopus)

Abstract

Two distinct ways of organizing fatty acid biosynthesis exist: the multifunctional type I fatty acid synthase (FAS) of mammals, fungi, and lower eukaryotes with activities residing on one or two polypeptides; and the dissociated type II FAS of prokaryotes, plastids, and mitochondria with individual activities encoded by discrete genes. The beta-ketoacyl [ACP] synthase (KAS) moiety of the mitochondrial FAS (mtKAS) is targeted by the antibiotic cerulenin and possibly by the other antibiotics inhibiting prokaryotic KASes: thiolactomycin, platensimycin, and the alpha-methylene butyrolactone, C75. The high degree of structural similarity between mitochondrial and prokaryotic KASes complicates development of novel antibiotics targeting prokaryotic KAS without affecting KAS domains of cytoplasmic FAS. KASes catalyze the C(2) fatty acid elongation reaction using either a Cys-His-His or Cys-His-Asn catalytic triad. Three KASes with different substrate specificities participate in synthesis of the C(16) and C(18) products of prokaryotic FAS. By comparison, mtKAS carries out all elongation reactions in the mitochondria. We present the X-ray crystal structures of the Cys-His-His-containing human mtKAS and its hexanoyl complex plus the hexanoyl complex of the plant mtKAS from Arabidopsis thaliana. The structures explain (1) the bimodal (C(6) and C(10)-C(12)) substrate preferences leading to the C(8) lipoic acid precursor and long chains for the membranes, respectively, and (2) the low cerulenin sensitivity of the human enzyme; and (3) reveal two different potential acyl-binding-pocket extensions. Rearrangements taking place in the active site, including subtle changes in the water network, indicate a change in cooperativity of the active-site histidines upon primer binding.
Udgivelsesdato: 2007-Feb

Originalsprog	Engelsk
Tidsskrift	Protein Science
Vol/bind	16
Udgave nummer	2
Sider (fra-til)	261-72
Antal sider	11
ISSN	0961-8368
DOI	https://doi.org/10.1110/ps.062473707
Status	Udgivet - 2007

Adgang til dokumentet

10.1110/ps.062473707

http://www.proteinscience.org/

Citationsformater

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title = "Structure of the human beta-ketoacyl [ACP] synthase from the mitochondrial type II fatty acid synthase.",

abstract = "Two distinct ways of organizing fatty acid biosynthesis exist: the multifunctional type I fatty acid synthase (FAS) of mammals, fungi, and lower eukaryotes with activities residing on one or two polypeptides; and the dissociated type II FAS of prokaryotes, plastids, and mitochondria with individual activities encoded by discrete genes. The beta-ketoacyl [ACP] synthase (KAS) moiety of the mitochondrial FAS (mtKAS) is targeted by the antibiotic cerulenin and possibly by the other antibiotics inhibiting prokaryotic KASes: thiolactomycin, platensimycin, and the alpha-methylene butyrolactone, C75. The high degree of structural similarity between mitochondrial and prokaryotic KASes complicates development of novel antibiotics targeting prokaryotic KAS without affecting KAS domains of cytoplasmic FAS. KASes catalyze the C(2) fatty acid elongation reaction using either a Cys-His-His or Cys-His-Asn catalytic triad. Three KASes with different substrate specificities participate in synthesis of the C(16) and C(18) products of prokaryotic FAS. By comparison, mtKAS carries out all elongation reactions in the mitochondria. We present the X-ray crystal structures of the Cys-His-His-containing human mtKAS and its hexanoyl complex plus the hexanoyl complex of the plant mtKAS from Arabidopsis thaliana. The structures explain (1) the bimodal (C(6) and C(10)-C(12)) substrate preferences leading to the C(8) lipoic acid precursor and long chains for the membranes, respectively, and (2) the low cerulenin sensitivity of the human enzyme; and (3) reveal two different potential acyl-binding-pocket extensions. Rearrangements taking place in the active site, including subtle changes in the water network, indicate a change in cooperativity of the active-site histidines upon primer binding. Udgivelsesdato: 2007-Feb",

author = "Christensen, {Caspar Elo} and Kragelund, {Birthe B} and {von Wettstein-Knowles}, Penny and Anette Henriksen",

note = "Keywords: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; Amino Acid Sequence; Binding Sites; Cerulenin; Crystallography, X-Ray; Fatty Acid Synthetase Complex; Humans; Mitochondrial Proteins; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Alignment; Sequence Homology, Amino Acid; Structure-Activity Relationship",

year = "2007",

doi = "10.1110/ps.062473707",

language = "English",

volume = "16",

pages = "261--72",

journal = "Protein Science",

issn = "0961-8368",

publisher = "Wiley-Blackwell",

number = "2",

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TY - JOUR

T1 - Structure of the human beta-ketoacyl [ACP] synthase from the mitochondrial type II fatty acid synthase.

AU - Christensen, Caspar Elo

AU - Kragelund, Birthe B

AU - von Wettstein-Knowles, Penny

AU - Henriksen, Anette

N1 - Keywords: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; Amino Acid Sequence; Binding Sites; Cerulenin; Crystallography, X-Ray; Fatty Acid Synthetase Complex; Humans; Mitochondrial Proteins; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Alignment; Sequence Homology, Amino Acid; Structure-Activity Relationship

PY - 2007

Y1 - 2007

N2 - Two distinct ways of organizing fatty acid biosynthesis exist: the multifunctional type I fatty acid synthase (FAS) of mammals, fungi, and lower eukaryotes with activities residing on one or two polypeptides; and the dissociated type II FAS of prokaryotes, plastids, and mitochondria with individual activities encoded by discrete genes. The beta-ketoacyl [ACP] synthase (KAS) moiety of the mitochondrial FAS (mtKAS) is targeted by the antibiotic cerulenin and possibly by the other antibiotics inhibiting prokaryotic KASes: thiolactomycin, platensimycin, and the alpha-methylene butyrolactone, C75. The high degree of structural similarity between mitochondrial and prokaryotic KASes complicates development of novel antibiotics targeting prokaryotic KAS without affecting KAS domains of cytoplasmic FAS. KASes catalyze the C(2) fatty acid elongation reaction using either a Cys-His-His or Cys-His-Asn catalytic triad. Three KASes with different substrate specificities participate in synthesis of the C(16) and C(18) products of prokaryotic FAS. By comparison, mtKAS carries out all elongation reactions in the mitochondria. We present the X-ray crystal structures of the Cys-His-His-containing human mtKAS and its hexanoyl complex plus the hexanoyl complex of the plant mtKAS from Arabidopsis thaliana. The structures explain (1) the bimodal (C(6) and C(10)-C(12)) substrate preferences leading to the C(8) lipoic acid precursor and long chains for the membranes, respectively, and (2) the low cerulenin sensitivity of the human enzyme; and (3) reveal two different potential acyl-binding-pocket extensions. Rearrangements taking place in the active site, including subtle changes in the water network, indicate a change in cooperativity of the active-site histidines upon primer binding. Udgivelsesdato: 2007-Feb

AB - Two distinct ways of organizing fatty acid biosynthesis exist: the multifunctional type I fatty acid synthase (FAS) of mammals, fungi, and lower eukaryotes with activities residing on one or two polypeptides; and the dissociated type II FAS of prokaryotes, plastids, and mitochondria with individual activities encoded by discrete genes. The beta-ketoacyl [ACP] synthase (KAS) moiety of the mitochondrial FAS (mtKAS) is targeted by the antibiotic cerulenin and possibly by the other antibiotics inhibiting prokaryotic KASes: thiolactomycin, platensimycin, and the alpha-methylene butyrolactone, C75. The high degree of structural similarity between mitochondrial and prokaryotic KASes complicates development of novel antibiotics targeting prokaryotic KAS without affecting KAS domains of cytoplasmic FAS. KASes catalyze the C(2) fatty acid elongation reaction using either a Cys-His-His or Cys-His-Asn catalytic triad. Three KASes with different substrate specificities participate in synthesis of the C(16) and C(18) products of prokaryotic FAS. By comparison, mtKAS carries out all elongation reactions in the mitochondria. We present the X-ray crystal structures of the Cys-His-His-containing human mtKAS and its hexanoyl complex plus the hexanoyl complex of the plant mtKAS from Arabidopsis thaliana. The structures explain (1) the bimodal (C(6) and C(10)-C(12)) substrate preferences leading to the C(8) lipoic acid precursor and long chains for the membranes, respectively, and (2) the low cerulenin sensitivity of the human enzyme; and (3) reveal two different potential acyl-binding-pocket extensions. Rearrangements taking place in the active site, including subtle changes in the water network, indicate a change in cooperativity of the active-site histidines upon primer binding. Udgivelsesdato: 2007-Feb

U2 - 10.1110/ps.062473707

DO - 10.1110/ps.062473707

M3 - Journal article

C2 - 17242430

SN - 0961-8368

VL - 16

SP - 261

EP - 272

JO - Protein Science

JF - Protein Science

IS - 2

ER -