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15  <p>  <p>
16  Different groups have created slightly differing notions of what is  Different groups have created slightly differing notions of what is
17  meant by <i>metabolic reconstruction</i>.  Within the context of this  meant by <i>metabolic reconstruction</i>.  Within the context of this
18  course, we might draw the following distinctions:  course, we draw the following distinctions:
19  <ol>  <ol>
20  <li>By an <b>informal metabolic reconstruction</b> we refer to  <li>By an <b>informal metabolic reconstruction</b> we refer to
21  <ul>  <ul>
# Line 36  Line 36 
36  encoding of the metabolic reaction network of the organism.  encoding of the metabolic reaction network of the organism.
37  </ol>  </ol>
38  That is, the informal reconstruction attempts to represent as much of  That is, the informal reconstruction attempts to represent as much of
39  the cellular machinery as possible, while the formal is usually  the cellular machinery as possible.  It provides a solid foundation
40  limited to metabolic reactions (and those reactions involving  from which the formal metabolic reconstruction can be based.  However,
41    the informal metabolic reaction has substantial by itself.  There are
42    many aspects of the phentotype that can be inferred by just
43    qualitative reasoning based upon the presence or absence of specific
44    subsystems or functional roles.  Further, many aspects of the
45    biochemistry (e.g., "missing genes") can be analyzed from just the
46    perspective of the informal metabolic reconstruction.
47    <p>
48    The formal is usually
49    limited to just metabolic reactions (and those reactions involving
50  generation or degradation of polymers are normally left out).  The  generation or degradation of polymers are normally left out).  The
51  output of a formal metabolic reconstruction will include detailed  output of a formal metabolic reconstruction will include detailed
52  encodings of both the reactions and the compounds that appear in the  encodings of both the reactions and the compounds that appear in the
53  metabolic network.  metabolic network.
54    >p>
55  These distinctions are ours, and are not commonly used.  These distinctions are ours, and are not commonly used.
56  We consider them unimportant, but useful.  We consider them unimportant, but useful.
57    
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95  present in the organism:  present in the organism:
96  <ol>  <ol>
97  <li>You should get a list of the subsystems with operational variants  <li>You should get a list of the subsystems with operational variants
98  from a SEED installation.  Note that the subsystems and genes that you  from a SEED installation.
99    The easiest way to do this involves starting from the first page
100    of the SEED, asking for <b>Statistics</b> for the genome you are
101    working on, and then (near the bottom of the page) clicking on <b>Show
102    subsystems</b>.
103    
104    Note that the subsystems and genes that you
105  get back may include both well-curated subsystems and  get back may include both well-curated subsystems and
106  poorly-constructed subsystems.  poorly-constructed subsystems.
107  <li>You should get colored versions of the KEGG maps (showing which  <li>You should get colored versions of the KEGG maps (showing which
# Line 113  Line 129 
129  synthesized, along with the starting point in each case.  Make sure  synthesized, along with the starting point in each case.  Make sure
130  that you compose a detailed list of outstanding questions.  that you compose a detailed list of outstanding questions.
131    
132  <h3>Synthesis of Nucleic Acids</h3>  <h3>Synthesis of Nucleotides</h3>
133    
134  We suggest that you next turn your attention to synthesis of nucleic  We suggest that you next turn your attention to synthesis of nucleotides.
135  acids.  Locate the appropriate KEGG charts and the relevant  Locate the appropriate KEGG charts and the relevant
136  subsystems.  Again, summarize the situation, along with outstanding  subsystems.  Again, summarize the situation, along with outstanding
137  questions.  questions.
138    
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152  have built formal metabolic reconstructions:  have built formal metabolic reconstructions:
153  <ul>  <ul>
154  <li><a  <li><a
155  href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12952533&query_hl=1>Escherichia coli</a>,  href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12952533&query_hl=1">Escherichia coli</a>,
156  <li><a  <li><a
157  href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15752426&query_hl=2"><i>Staphylococcus  href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15752426&query_hl=2"><i>Staphylococcus
158  aureus</i></a> and  aureus</i></a> and
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165  where each reaction includes precise substrates, products and  where each reaction includes precise substrates, products and
166  (possibly) a required enzyme.  (possibly) a required enzyme.
167    
168  <h2>Begin from the Informal Metabolic Reconstruction</h2>  <h3>Begin from the Informal Metabolic Reconstruction</h2>
169    
170  You should begin from the informal metabolic reconstruction and  You should begin from the informal metabolic reconstruction and
171  accumulate the reactions and compounds implied by the operational  accumulate the reactions and compounds implied by the operational
172  variants of the subsystems.This can be done using  variants of the subsystems.This can be done by starting from the first page
173  <a href=http://TheSEED.uchicago.edu/FIG/build_formal_reconstruction.cgi>  of the SEED, asking for <b>Statistics</b> for the genome you are
174  a tool to produce an initial estimate</a>.  You will be asked to  working on, and then (near the bottom of the page) clicking on <b>Show
175  select a genome, and the result will be a list of compounds and  reactions</b>.
176  reactions implied by the subsystems that have been developed.  This tool produces an initial estimate of the reaction set.
177    <p>
178    This initial set is far from complete and some of the reactions
179    presented will be encoded improperly.  Before continuing let us just
180    ponder what a "complete and accurated formal metabolic reconstruction"
181    would contain:
182    <ul>
183    <li>It would contain all of the metabolic reactions.  For many
184    purposes it might be useful to exclude synthesis and degradation of
185    polymers.  On the other hand, for whole organism modeling, it becomes
186    necessary to estimate the compounds that can be transported into and
187    out of the cell.  This is quite difficult.  For the purposes of this
188    class you should ignore the reactions relating to polymers, and you
189    should ignore the issue of exactly what can be transported.
190    
191    <li>The reaction set should not contain <i>class reactions</i> (those
192    in which the substrates and products are not specific).
193    
194    <li>You can construct a list of compounds that must be
195    present based on this incomplete reaction set.  To get the initial
196    approximation of this set, ...
197    
198    <li>From the list of reactions and compounds, you should be able to
199    produce a set of compounds that exist as substrates for one or more
200    reactions, but not as products.  This computation cannot be done
201    accurately without knowing which reactions are reversible.  This can
202    be done using ...
203    
204    <li>Finally, you should produce a list of compounds that exist as
205    products, but not as substrates.  This can be done using ...
206    </ul>
207    
208    <p>
209    For the purposes of this class, construction of this initial, crude
210    formal metabolic reconstruction is both the best you can do and a
211    major achievement.  To refine it into a useful and accurate summary of
212    the metabolism of the cell is something that a person might work a
213    lifetime on.
214    
215    <h2>Summary</h2>
216    
217    The object of this portion of the class will be to development both an
218    initial <b>informal metabolic reconstruction</b> and a <b>formal
219    metabolic reconstruction</b> for some specific organism.  If you can
220    successfully achieve this, you will have done something that was
221    almost impossible even a few years ago.  If you study and reflect on
222    what you accomplish, it will form a starting point for deepening your
223    understanding of microbial physiology and biochemistry.

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