Bioinorganic Chemistry of Carbon Monoxide Dehydrogenase View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

1993-2012

FUNDING AMOUNT

2694071 USD

ABSTRACT

DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the catalytic mechanism of acetyl-CoA synthase/carbon monoxide dehydrogenase (ACS/CODH), one of the most complex metalloenzymes known. This oxygen-sensitive bifunctional enzyme contains two nickel-iron-sulfur cluster active-sites which are unique in biology. They are connected by a protein tunnel through which CO migrates from one site to the other, controlled by a conformational change which is intricately correlated to the catalytic mechanism. One of the Ni ions may be reduced to a zero-valent state during reductive activation, and this ion may bind methyl and acetyl groups during catalysis;thus the enzyme catalyzes an organometallic reaction mechanism which is unique in biology. Indeed two specific aims for the next four years are to obtain direct physical evidence for the zero-valent state and for the Ni-bound methyl and acetyl adducts. Another aim is to determine the factors that control the conformation of the protein and to understand how protein conformation is choreographed with catalysis. For reasons that are poorly understood, the enzyme is heterogenous in that only ~ 30% of ACS/CODH molecules in a population are catalytically functional. A fourth aim is to determine the origin of this heterogeneity and eliminate it if possible. A cadre of spectrocopic methods will be used, including EPR and M"ssbauer spectroscopy, NMR, X-ray absorption, and fluoresence. Stopped-flow kinetics and site-directed mutagenesis will also be used. PUBLIC HEALTH RELEVANCE: Clostridium difficile, which contains this enzyme ACS/CODH, causes antibiotic-associated colitis, toxic megacolon, intestinal perforations and even death in humans. Our mechanistic study of ACS/CODH will help define the metabolic roles played by the enzyme in this pathogen, and identify strategies for preventing the proliferation of C. difficile in intestines. Also, ACS/CODH is important in environmental health, as it removes CO from the atmosphere and degrades TNT from abandoned military sites. ACS/CODH is involved in C1 metabolism and it contains a sophisticated tunnel through which CO migrates, impacting the field of metabolic channeling. A number of other metalloenzymes are heterogeneous in terms of catalytic function, and the studies described here might contribute to elucidating the reasons for such "half-sites" reactivity. More... »

URL

http://projectreporter.nih.gov/project_info_description.cfm?aid=8104275

Related SciGraph Publications

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/2206", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "type": "DefinedTerm"
      }
    ], 
    "amount": {
      "currency": "USD", 
      "type": "MonetaryAmount", 
      "value": "2694071"
    }, 
    "description": "DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the catalytic mechanism of acetyl-CoA synthase/carbon monoxide dehydrogenase (ACS/CODH), one of the most complex metalloenzymes known. This oxygen-sensitive bifunctional enzyme contains two nickel-iron-sulfur cluster active-sites which are unique in biology. They are connected by a protein tunnel through which CO migrates from one site to the other, controlled by a conformational change which is intricately correlated to the catalytic mechanism. One of the Ni ions may be reduced to a zero-valent state during reductive activation, and this ion may bind methyl and acetyl groups during catalysis;thus the enzyme catalyzes an organometallic reaction mechanism which is unique in biology. Indeed two specific aims for the next four years are to obtain direct physical evidence for the zero-valent state and for the Ni-bound methyl and acetyl adducts. Another aim is to determine the factors that control the conformation of the protein and to understand how protein conformation is choreographed with catalysis. For reasons that are poorly understood, the enzyme is heterogenous in that only ~ 30% of ACS/CODH molecules in a population are catalytically functional. A fourth aim is to determine the origin of this heterogeneity and eliminate it if possible. A cadre of spectrocopic methods will be used, including EPR and M\"ssbauer spectroscopy, NMR, X-ray absorption, and fluoresence. Stopped-flow kinetics and site-directed mutagenesis will also be used. PUBLIC HEALTH RELEVANCE: Clostridium difficile, which contains this enzyme ACS/CODH, causes antibiotic-associated colitis, toxic megacolon, intestinal perforations and even death in humans. Our mechanistic study of ACS/CODH will help define the metabolic roles played by the enzyme in this pathogen, and identify strategies for preventing the proliferation of C. difficile in intestines. Also, ACS/CODH is important in environmental health, as it removes CO from the atmosphere and degrades TNT from abandoned military sites. ACS/CODH is involved in C1 metabolism and it contains a sophisticated tunnel through which CO migrates, impacting the field of metabolic channeling. A number of other metalloenzymes are heterogeneous in terms of catalytic function, and the studies described here might contribute to elucidating the reasons for such \"half-sites\" reactivity.", 
    "endDate": "2012-06-30T00:00:00Z", 
    "funder": {
      "id": "https://www.grid.ac/institutes/grid.280785.0", 
      "type": "Organization"
    }, 
    "id": "sg:grant.2513561", 
    "identifier": [
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "2513561"
        ]
      }, 
      {
        "name": "nih_id", 
        "type": "PropertyValue", 
        "value": [
          "R01GM046441"
        ]
      }
    ], 
    "inLanguage": [
      "en"
    ], 
    "keywords": [
      "death", 
      "sulfur clusters", 
      "enzyme ACS/CODH", 
      "humans", 
      "factors", 
      "enzyme", 
      "number", 
      "other metalloenzymes", 
      "CODH", 
      "spectrocopic methods", 
      "acetyl adducts", 
      "population", 
      "conformational changes", 
      "description", 
      "pathogens", 
      "origin", 
      "long-term objective", 
      "antibiotic-associated colitis", 
      "strategies", 
      "methyl", 
      "carbon monoxide dehydrogenase", 
      "years", 
      "intestinal perforation", 
      "applicants", 
      "Ni ions", 
      "direct physical evidence", 
      "acetyl-CoA synthase/carbon monoxide dehydrogenase", 
      "fourth aim", 
      "intestine", 
      "aim", 
      "biology", 
      "Ni", 
      "ACS", 
      "proliferation", 
      "specific aim", 
      "fluoresence", 
      "catalysis", 
      "field", 
      "ray absorption", 
      "public health relevance", 
      "conformation", 
      "ACS/CODH molecules", 
      "sites", 
      "study", 
      "atmosphere", 
      "C1 metabolism", 
      "military sites", 
      "terms", 
      "organometallic reaction mechanisms", 
      "catalytic mechanism", 
      "ions", 
      "cadre", 
      "C. difficile", 
      "EPR", 
      "TNT", 
      "reactivity", 
      "zero-valent state", 
      "metabolic channeling", 
      "stopped-flow kinetics", 
      "reason", 
      "nickel-iron", 
      "toxic megacolon", 
      "reductive activation", 
      "environmental health", 
      "project", 
      "protein", 
      "oxygen-sensitive bifunctional enzyme", 
      "acetyl group", 
      "catalytic function", 
      "mutagenesis", 
      "NMR", 
      "protein conformation", 
      "metabolic role", 
      "complex metalloenzymes", 
      "M\"ssbauer spectroscopy", 
      "Clostridium difficile", 
      "Co", 
      "sophisticated tunnel", 
      "heterogeneity", 
      "bioinorganic chemistry", 
      "mechanistic studies", 
      "ACS/CODH", 
      "protein tunnels"
    ], 
    "name": "Bioinorganic Chemistry of Carbon Monoxide Dehydrogenase", 
    "recipient": [
      {
        "id": "https://www.grid.ac/institutes/grid.264756.4", 
        "type": "Organization"
      }, 
      {
        "affiliation": {
          "id": "https://www.grid.ac/institutes/grid.264756.4", 
          "name": "TEXAS A&M UNIVERSITY", 
          "type": "Organization"
        }, 
        "familyName": "LINDAHL", 
        "givenName": "PAUL A.", 
        "id": "sg:person.0612027106.77", 
        "type": "Person"
      }, 
      {
        "member": "sg:person.0612027106.77", 
        "roleName": "PI", 
        "type": "Role"
      }
    ], 
    "sameAs": [
      "https://app.dimensions.ai/details/grant/grant.2513561"
    ], 
    "sdDataset": "grants", 
    "sdDatePublished": "2019-03-07T12:17", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com.uberresearch.data.processor/core_data/20181219_192338/projects/base/nih_projects_9.xml.gz", 
    "startDate": "1993-04-01T00:00:00Z", 
    "type": "MonetaryGrant", 
    "url": "http://projectreporter.nih.gov/project_info_description.cfm?aid=8104275"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/grant.2513561'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/grant.2513561'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/grant.2513561'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/grant.2513561'


 

This table displays all metadata directly associated to this object as RDF triples.

127 TRIPLES      19 PREDICATES      105 URIs      97 LITERALS      5 BLANK NODES

Subject Predicate Object
1 sg:grant.2513561 schema:about anzsrc-for:2206
2 schema:amount Ne3023737c4fe403fbfb1b7b6a8d8fb94
3 schema:description DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the catalytic mechanism of acetyl-CoA synthase/carbon monoxide dehydrogenase (ACS/CODH), one of the most complex metalloenzymes known. This oxygen-sensitive bifunctional enzyme contains two nickel-iron-sulfur cluster active-sites which are unique in biology. They are connected by a protein tunnel through which CO migrates from one site to the other, controlled by a conformational change which is intricately correlated to the catalytic mechanism. One of the Ni ions may be reduced to a zero-valent state during reductive activation, and this ion may bind methyl and acetyl groups during catalysis;thus the enzyme catalyzes an organometallic reaction mechanism which is unique in biology. Indeed two specific aims for the next four years are to obtain direct physical evidence for the zero-valent state and for the Ni-bound methyl and acetyl adducts. Another aim is to determine the factors that control the conformation of the protein and to understand how protein conformation is choreographed with catalysis. For reasons that are poorly understood, the enzyme is heterogenous in that only ~ 30% of ACS/CODH molecules in a population are catalytically functional. A fourth aim is to determine the origin of this heterogeneity and eliminate it if possible. A cadre of spectrocopic methods will be used, including EPR and M"ssbauer spectroscopy, NMR, X-ray absorption, and fluoresence. Stopped-flow kinetics and site-directed mutagenesis will also be used. PUBLIC HEALTH RELEVANCE: Clostridium difficile, which contains this enzyme ACS/CODH, causes antibiotic-associated colitis, toxic megacolon, intestinal perforations and even death in humans. Our mechanistic study of ACS/CODH will help define the metabolic roles played by the enzyme in this pathogen, and identify strategies for preventing the proliferation of C. difficile in intestines. Also, ACS/CODH is important in environmental health, as it removes CO from the atmosphere and degrades TNT from abandoned military sites. ACS/CODH is involved in C1 metabolism and it contains a sophisticated tunnel through which CO migrates, impacting the field of metabolic channeling. A number of other metalloenzymes are heterogeneous in terms of catalytic function, and the studies described here might contribute to elucidating the reasons for such "half-sites" reactivity.
4 schema:endDate 2012-06-30T00:00:00Z
5 schema:funder https://www.grid.ac/institutes/grid.280785.0
6 schema:identifier Nb38b2a58bc9b44f5baee69056fe15020
7 Nf53bb49a897444cb837e69932e570cb0
8 schema:inLanguage en
9 schema:keywords ACS
10 ACS/CODH
11 ACS/CODH molecules
12 C. difficile
13 C1 metabolism
14 CODH
15 Clostridium difficile
16 Co
17 EPR
18 M"ssbauer spectroscopy
19 NMR
20 Ni
21 Ni ions
22 TNT
23 acetyl adducts
24 acetyl group
25 acetyl-CoA synthase/carbon monoxide dehydrogenase
26 aim
27 antibiotic-associated colitis
28 applicants
29 atmosphere
30 bioinorganic chemistry
31 biology
32 cadre
33 carbon monoxide dehydrogenase
34 catalysis
35 catalytic function
36 catalytic mechanism
37 complex metalloenzymes
38 conformation
39 conformational changes
40 death
41 description
42 direct physical evidence
43 environmental health
44 enzyme
45 enzyme ACS/CODH
46 factors
47 field
48 fluoresence
49 fourth aim
50 heterogeneity
51 humans
52 intestinal perforation
53 intestine
54 ions
55 long-term objective
56 mechanistic studies
57 metabolic channeling
58 metabolic role
59 methyl
60 military sites
61 mutagenesis
62 nickel-iron
63 number
64 organometallic reaction mechanisms
65 origin
66 other metalloenzymes
67 oxygen-sensitive bifunctional enzyme
68 pathogens
69 population
70 project
71 proliferation
72 protein
73 protein conformation
74 protein tunnels
75 public health relevance
76 ray absorption
77 reactivity
78 reason
79 reductive activation
80 sites
81 sophisticated tunnel
82 specific aim
83 spectrocopic methods
84 stopped-flow kinetics
85 strategies
86 study
87 sulfur clusters
88 terms
89 toxic megacolon
90 years
91 zero-valent state
92 schema:name Bioinorganic Chemistry of Carbon Monoxide Dehydrogenase
93 schema:recipient Nd93e844257b44c368004116a1e2a5c7e
94 sg:person.0612027106.77
95 https://www.grid.ac/institutes/grid.264756.4
96 schema:sameAs https://app.dimensions.ai/details/grant/grant.2513561
97 schema:sdDatePublished 2019-03-07T12:17
98 schema:sdLicense https://scigraph.springernature.com/explorer/license/
99 schema:sdPublisher N4ef7bafa40ee4c92a0ac6eb106313126
100 schema:startDate 1993-04-01T00:00:00Z
101 schema:url http://projectreporter.nih.gov/project_info_description.cfm?aid=8104275
102 sgo:license sg:explorer/license/
103 sgo:sdDataset grants
104 rdf:type schema:MonetaryGrant
105 N4ef7bafa40ee4c92a0ac6eb106313126 schema:name Springer Nature - SN SciGraph project
106 rdf:type schema:Organization
107 Nb38b2a58bc9b44f5baee69056fe15020 schema:name dimensions_id
108 schema:value 2513561
109 rdf:type schema:PropertyValue
110 Nd93e844257b44c368004116a1e2a5c7e schema:member sg:person.0612027106.77
111 schema:roleName PI
112 rdf:type schema:Role
113 Ne3023737c4fe403fbfb1b7b6a8d8fb94 schema:currency USD
114 schema:value 2694071
115 rdf:type schema:MonetaryAmount
116 Nf53bb49a897444cb837e69932e570cb0 schema:name nih_id
117 schema:value R01GM046441
118 rdf:type schema:PropertyValue
119 anzsrc-for:2206 schema:inDefinedTermSet anzsrc-for:
120 rdf:type schema:DefinedTerm
121 sg:person.0612027106.77 schema:affiliation https://www.grid.ac/institutes/grid.264756.4
122 schema:familyName LINDAHL
123 schema:givenName PAUL A.
124 rdf:type schema:Person
125 https://www.grid.ac/institutes/grid.264756.4 schema:name TEXAS A&M UNIVERSITY
126 rdf:type schema:Organization
127 https://www.grid.ac/institutes/grid.280785.0 schema:Organization
 




Preview window. Press ESC to close (or click here)


...