The Diverse Roles of the Mucin Gene Cluster Located on Chromosome 11p15.5 in Colorectal Cancer

<div>The clb gene cluster encodes the biosynthesis of metabolites known as precolibactins and colibactins. The clb pathway is found in gut commensal E. coli, and clb metabolites are thought to initiate colorectal cancer via DNA cross-linking. Precolibactin 886 (1) is one of the most complex isolated clb metabolites; it contains a 15-atom macrocycle and an unusual 5-hydroxy-3-oxazoline ring. Here we report confirmation of the structural assignment via a biomimetic synthesis of precolibactin 886 (1) proceeding through the amino alcohol 9. Double oxidation of 9 afforded the unstable α-ketoimine 2 which underwent macrocyclization to precolibactin 886 (1) upon HPLC purification (3% from 9). Studies of the putative precolibactin 886 (1) biosynthetic precursor 2, the model α-ketoimine 25, and the α-dicarbonyl 26 revealed that these compounds are susceptible to nucleophilic rupture of the C36–C37 bond. Moreover, cleavage of 2 produces other known clb metabolites or biosynthetic intermediates. This unexpected reactivity explains the difficulties in isolating full clb metabolites and accounts for the structure of a recently identified colibactin–adenine adduct. The colibactin peptidase ClbP deacylates synthetic precolibactin 886 (1) to form a non-genotoxic pyridone, suggesting precolibactin 886 (1) lies off-path of the major biosynthetic route.</div>

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The mouse secreted gel-forming mucin gene cluster

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression ◽

10.1016/j.bbaexp.2004.01.001 ◽

2004 ◽

Vol 1676 (3) ◽

pp. 240-250 ◽

Cited By ~ 33

Author(s):

Fabienne Escande ◽

Nicole Porchet ◽

Annie Bernigaud ◽

Danièle Petitprez ◽

Jean-Pierre Aubert ◽

...

Keyword(s):

Gene Cluster ◽

Mucin Gene

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Genomic organization of the 3′-region of the human MUC5AC mucin gene: additional evidence for a common ancestral gene for the 11p15.5 mucin gene family

Biochemical Journal ◽

10.1042/bj3320729 ◽

1998 ◽

Vol 332 (3) ◽

pp. 729-738 ◽

Cited By ~ 37

Author(s):

Marie-Pierre BUISINE ◽

Jean-Luc DESSEYN ◽

Nicole PORCHET ◽

Pierre DEGAND ◽

Anne LAINE ◽

...

Keyword(s):

Gene Family ◽

Genomic Organization ◽

Splice Sites ◽

Ancestral Gene ◽

Remarkable Similarity ◽

Mucin Gene ◽

Isolation And Characterization ◽

Entire Sequence ◽

Chromosome 11P15.5

The human mucin gene MUC5AC is mapped clustered with MUC2, MUC5B and MUC6 on chromosome 11p15.5. We report here the isolation and characterization of a genomic cosmid clone, designated ELO9, spanning the 3´-region of MUC5AC and the 5´-region of MUC5B, allowing us to conclude that MUC5AC and MUC5B have the same transcriptional orientation. We determined the genomic organization and the entire sequence of the 3´-region of MUC5AC. The comparative molecular analysis of MUC5AC and MUC5B points to a remarkable similarity in the size and the distribution of exons, and in the type of splice sites, supporting the notion that MUC5AC and MUC5B have evolved from a single common ancestral gene. The derivation of the four genes of the 11p15.5 mucin gene family from a single ancestral gene is discussed.

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Abstract 3411: Role of mucin gene variations in microRNA binding sites in modulating colorectal cancer susceptibility and clinical outcomes

10.1158/1538-7445.am2016-3411 ◽

2016 ◽

Author(s):

Petra Bendova ◽

Veronika Vymetalkova ◽

Barbara Pardini ◽

Fabio Rosa ◽

Cornelia di Gaetano ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Outcomes ◽

Binding Sites ◽

Cancer Susceptibility ◽

Mucin Gene

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Synthesis and Reactivity of Precolibactin 886

10.26434/chemrxiv.7849151.v1 ◽

2019 ◽

Author(s):

Seth Herzon ◽

Alan R. Healy ◽

kevin wernke ◽

Chung Sub Kim ◽

Nicholas Lees ◽

...

Keyword(s):

Colorectal Cancer ◽

Gene Cluster ◽

Amino Alcohol ◽

Biomimetic Synthesis ◽

Cross Linking ◽

E Coli ◽

Hplc Purification ◽

Structural Assignment ◽

Biosynthetic Precursor ◽

Double Oxidation

<div>The clb gene cluster encodes the biosynthesis of metabolites known as precolibactins and colibactins. The clb pathway is found in gut commensal E. coli, and clb metabolites are thought to initiate colorectal cancer via DNA cross-linking. Precolibactin 886 (1) is one of the most complex isolated clb metabolites; it contains a 15-atom macrocycle and an unusual 5-hydroxy-3-oxazoline ring. Here we report confirmation of the structural assignment via a biomimetic synthesis of precolibactin 886 (1) proceeding through the amino alcohol 9. Double oxidation of 9 afforded the unstable α-ketoimine 2 which underwent macrocyclization to precolibactin 886 (1) upon HPLC purification (3% from 9). Studies of the putative precolibactin 886 (1) biosynthetic precursor 2, the model α-ketoimine 25, and the α-dicarbonyl 26 revealed that these compounds are susceptible to nucleophilic rupture of the C36–C37 bond. Moreover, cleavage of 2 produces other known clb metabolites or biosynthetic intermediates. This unexpected reactivity explains the difficulties in isolating full clb metabolites and accounts for the structure of a recently identified colibactin–adenine adduct. The colibactin peptidase ClbP deacylates synthetic precolibactin 886 (1) to form a non-genotoxic pyridone, suggesting precolibactin 886 (1) lies off-path of the major biosynthetic route.</div>

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