Amarnath Gupta

1
Department of Computer Science Engineering
University of California, San DiegoCSE-291
Ontologies in Data IntegrationSpring
2004Ontologies and Biological Pathways

• Amarnath Gupta

2
So, What is an Ontology Again?

• From previous classes
• Sowa The subject of ontology is the study of
  the categories of things that exist or may exist
  in some domain. The product of such a study,
  called an ontology, is a catalog of the types of
  things that are assumed to exist in a domain of
  interest D from the perspective of a person who
  uses a language L for the purpose of talking
  about D A formal ontology is specified by a
  collection of names for concept and relation
  types organized in a partial ordering by the
  type-subtype relation.
• Guarino Theory of formal distinctions
• among things
• among relations
• Basic tools
• Theory of parthood
• Theory of integrity
• Theory of identity
• Theory of dependence

Is this good enough to characterize all concepts
and relations?
3
Description Logics as Ontology Frameworks

• You have learnt about Description Logics
• DLs allow you to do the following

4
Property Frames in DLs

• Some Description Logics like SHOQ(D)1, a
  progenitor of OWL, allow
• Roles or properties to be more powerful
• If R and S are roles, one can specify a role box
  that contains
• role equivalence axioms ?component_of.? ?
  ?part_of.?
• role inverses (not present in SHOQ, but present
  in SHIQ)
• role inclusion axioms R ? S
• role transitivity axioms Trans(R)
• Thus one can construct role hierarchies in
  addition to concept lattices

1Ian Horrocks and U. Sattler. Ontology Reasoning
for the Semantic Web. In B. Nebel, editor, Proc.
of the 17th Int. Joint Conf. on Articial
Intelligence (IJCAI'01), Morgan Kaufmann, pages
199-204, 2001.
5
Thing-Centric Ontologies

• Now lets try these
• sky
• blue_sky sky ? ? has_color.blue
• cloudy_sky sky ? ? covered_by.cloud
• rain
• acid_rain ? rain
• acid_rain_from_cloudy_sky acid_rain ? ?
  drops_from.cloudy_sky
• Is this reasonable?
• How about these?
• year
• quarter ? ??4 part_of.year
• mid_term ? exam ? final_test ? ?
  occurs_in.quarter
• Is it working? Why?

Not every concept and relation is thing-centric!!
6
Ontologies for Processes, Events, Time

• Temporal Description Logic2
• Allens interval relations

2A. Artale and E. Franconi. A temporal
description logic for reasoning about actions and
plans. Journal of Artificial Intelligence
Research, 9463--506, 1998
7
Temporal Description Logic

• Ingredients
• non-temporal concepts E
• temporal concepts C
• things that change their state
• temporal qualifier C_at_X where X is a temporal
  variable
• temporal constraints Tc
• (X (R) Y) where
• X is any temporal variable or the NOW interval
  
• R can be Allens interval relations or an
  expression composed from it
• existential quantifiers
• ? (X) Tc.C
• selections pE where p is
• an atomic feature f
• a parameterized feature f

8
Applying Temporal DL
translocation

in-nucleus(protein)
in-cytoplasm(protein)
y
x

• Translocation of a protein
• translocation ??(x y)(x m )( m y) ((Protein
  InCytoplasm)_at_x ? (Protein InNucleus)_at_y)
• Protein is the formal parameter of this action
• States of the Protein are treated as though they
  are different type assignments for the same
  variable
• The above is a definition of the term
  translocation
• Now we can have an assertion (meaning data) of
  the form
• translocation(tp1, MAPK-translocation), i.e., of
  the form translocation(Interval, Action) to
  designate a specific case, thus implying
• translocation(i, a) ? ?p. Protein(a, p) ?
• ?j,l.
  (InCytoplasm(j,p) ? InNucleus(l,p) ? m(j,i) ?
  m(i,l))

9
Applying Temporal DL

• Some identities
• ? x (x a ). C_at_x ? xy (y mi )(x mi y). C_at_x
• ? x (x d ). C_at_x ? xy (y s )(x f y). C_at_x
• ? x (x o ). C_at_x ? xy (y s )(x fi y). C_at_x
• A little more complex case

We only really need the relations s, f and mi
GRB2_secondary_response

GRB2_binding
PTK_ligand_binding
w
z
tyrosin_phosphorylated
y
autophosphorylation
tyrosin
y
x
tyrosin_p ? ? x (x o ). (tyrosin_at_x ?
autophosphorylation) GRB2_s_r ? ? (y z w)(y b
w)(z b w) (tyrosine_p_at_y ? PTK_l_b_at_z ? GRB2_b_at_w )
10
Applying Temporal DL

• More features of the temporal DL
• path p ? q
• Protein? bound should be interpreted as
• ? a,p,i,o1 Protein(a, p, i) ? bound(i, p, o1)
• Agreement operator ?
• (Protein? bound ? Receptor)_at_y means at the
  interval y the object to which Protein is bound
  is Receptor)
• Substitution
• Suppose A ? ? (x y z w)() is an axiom and
• B ? ? (x u v)() is another axiom whose body is
  a part of A
• The temporal substitutive qualifier (Bx_at_v)
  renames within the defined B action the variable
  x to w and it is a way of making coreference
  between two temporal variables, while the
  temporal constraints peculiar to the renamed
  variable x are inherited by the substituting
  interval w. This will eliminate x from A.
• This can be used to define one temporal concept
  in terms of another

11
And now on to Biological Pathways

• The goals are
• to comprehend what we need to represent before we
  think about how to represent them
• what computations we can do with them

12
What are Pathways?

• A pathway is a set of linked biological
  components interacting with each other over time
  to generate a biological effect
• A component in a pathway can often be broken down
  into a finer level of interacting components that
  finally get to single biochemical reactions
• When people talk about pathways they refer to
• signal transduction networks
• metabolic pathways
• gene regulatory pathways
• protein-protein interaction networks

13
Signal Transduction Networks

• What is Signal Transduction?

Process by which a cell converts one kind of
signal or stimulus into another
14
The Big Picture

• How do organisms communicate with their
  environment?
• How do cells exchange information?
• What information needs to be exchanged?
• What is the currency of information?

15
Events

• Stimuli
• Synthesis of signaling molecule by the signaling
  cell.
• Release of signaling molecule by the signaling
  cell.
• Transport of the signal to the target cell.
• Detection of the signal by a specific receptor
  protein.
• Responses
• Reception First messenger extracellular
  molecule (signal), binds to a receptor.
• Transduction
• Amplification Binding activates receptor
  protein, which then activates relay protein.
• Conversion Relay protein stimulates another
  membrane protein which acts as an effector
  (effects changes in cell).
• Induction/Response Effector protein enzyme
  that produces a secondary messenger (cytoplasmic
  molecule that triggers metabolic and/or
  structural responses within cell).
• Removal of the signal, often terminating the
  cellular response.

16
Types of Signals

• Extracellular
• Signal molecules are specific to their receptors
• Receptors, usually proteins, have N terminal face
  outwards and C terminal inside the cell.
• When bound to a signal molecule, a receptor
  changes its conformation

17
Types of Signals

• Intracellular
• Mostly triggered by the extracellular signal
• Converts the extracellular signal into an
  intracellular signal
• Eg. - G protein, GTPase, cAMP, Ca, Kinases,
  phosphatases and many more
• Also called second messengers

18
Types of Signals

• Intercellular
• Extracellular signalling
• Endocrinology
• Types
• Endocrine Travel through blood
• Paracrine In the vicinity
• Autocrine Same cell type
• Juxtacrine Along cell membranes

19
Types of Signals

• Hormones
• Between cells or tissues within an individual
• Process
• Synthesis ? Storage and secretion ? Transport ?
  Recognition of hormone by its receptor ? change
  in receptor shape ? Relay and amplification of
  signal ? Response
• Sending cell is a specialized cell while the
  receiving can be of any type
• A single hormone can have many receptors for
  different pathways or many hormones can have same
  receptor to invoke same pathway
• Two classes of hormone receptors
• Membrane associated
• Cytoplasmic

20
Cellular Response

• depends on the particular signaling pathways -
  may involve changes in
• cell cycle progression
• gene expression
• protein trafficking
• cell migration
• cytoskeleton architecture
• adhesion
• metabolism
• cell survival

21
Example RAS-RAF-MEK-MAPK pathways

• It should be noted that the RAS-RAF-MEK-MAPK
  pathway is only one example of so called MAPK
  (Mitogen-Activated Protein Kinase) pathways .
• Two other mammalian MAPK pathways involving JNK1
  and p38, are involved in stress responses (they
  are also MAPK pathways).

22
RAS-RAF-MEK-MAPK
Ligand binds receptor PTK
23
RAS-RAF-MEK-MAPK
Ligand binds receptor PTK Autophosphorylation
on tyrosine
24
RAS-RAF-MEK-MAPK
Ligand binds receptor PTK Autophosphorylation
on tyrosine GRB2 (a SH2- and SH3-containing
protein) binds to the receptor phosphotyrosine
motif Y-V/L-N-X via its SH2 domain
25
RAS-RAF-MEK-MAPK
Ligand binds receptor PTK Autophosphorylation
on tyrosine GRB2 (a SH2- and SH3-containing
protein) binds to the receptor phosphotyrosine
motif Y-V/L-N-X via its SH2 domain The SH3 of
GRB2 binds constitutively to the proline-rich
sequence in the C-terminus of SOS (a guanine
nucleotide exchange factor for RAS).
SOS
26
RAS-RAF-MEK-MAPK
Recruitment of SOS to the close proximity of
RAS in the membrane
SOS
27
RAS-RAF-MEK-MAPK
RAS becomes activated by exchanging GDP for GTP
RAS
GTP
GDP
SOS
28
RAS-RAF-MEK-MAPK
The RAS-GTP effector domain interacts with the
N-terminal regulatory region of the RAF
(serine/threonine protein kinase), hence
recruiting RAF to the membrane
RAS
GTP
RAF
SOS
29
RAS-RAF-MEK-MAPK
Activation of RAF (most likely by
phosphorylation of RAF and binding to the
scaffold protein 14-3-3)
RAS
GTP
14-3-3
RAF
SOS
30
RAS-RAF-MEK-MAPK
Activation of RAF (most likely by
phosphorylation of RAF and binding to the
scaffold protein 14-3-3)
RAS
GTP
14-3-3
RAF
SOS
31
RAS-RAF-MEK-MAPK
Activated RAF in turn activates MEK (also
called MAPK kinase a dual specificity kinase) by
phosphorylation on two conserved serine residues
in MEK.
RAS
GTP
14-3-3
RAF
SOS
MEK
32
RAS-RAF-MEK-MAPK
Activated RAF in turn activates MEK (also
called MAPK kinase a dual specificity kinase) by
phosphorylation on two conserved serine residues
in MEK.
RAS
GTP
14-3-3
RAF
SOS
MEK
33
RAS-RAF-MEK-MAPK
Activated MEK activates MAPK (a
serine/threonine protein kinase) by
phosphorylation of conserved threonine and
tyrosine residues.
RAS
GTP
14-3-3
RAF
SOS
MEK
MAPK
34
RAS-RAF-MEK-MAPK
Activated MEK activates MAPK (a
serine/threonine protein kinase) by
phosphorylation of conserved threonine and
tyrosine residues.
RAS
GTP
14-3-3
RAF
SOS
MEK
MAPK
35
RAS-RAF-MEK-MAPK
Activated MAPK phosphorylates a number of
substrates in the plasma membrane and the
cytoplasm
RAS
GTP
14-3-3
RAF
SOS
MEK
Substrates
MAPK
Substrates
36
RAS-RAF-MEK-MAPK

• Activated MAPK phosphorylates a number of
  substrates in the plasma membrane and the
  cytoplasm
• It also translocated into the nucleus(within
  min) where it phosphorylates nuclear
  transcription factors.

RAS
GTP
14-3-3
RAF
SOS
MEK
MAPK
Substrates
37
RAS-RAF-MEK-MAPK

• Activated MAPK phosphorylates a number of
  substrates in the plasma membrane and the
  cytoplasm
• It also translocated into the nucleus(within
  min) where it phosphorylates nuclear
  transcription factors.

RAS
GTP
14-3-3
RAF
SOS
MEK
Substrates
38
RAS-RAF-MEK-MAPK

• Activated MAPK phosphorylates a number of
  substrates in the plasma membrane and the
  cytoplasm
• It also translocated into the nucleus(within
  min) where it phosphorylates nuclear
  transcription factors.

RAS
GTP
14-3-3
RAF
SOS
MEK
MAPK
Substrates
39
RAS-RAF-MEK-MAPK

• Activated MAPK phosphorylates a number of
  substrates in the plasma membrane and the
  cytoplasm
• It also translocated into the nucleus(within
  min) where it phosphorylates nuclear
  transcription factors.

RAS
GTP
14-3-3
RAF
SOS
MEK
MAPK
Substrates
40
RAS-RAF-MEK-MAPK

• Activated MAPK phosphorylates a number of
  substrates in the plasma membrane and the
  cytoplasm
• It also translocated into the nucleus(within
  minutes) where it phosphorylates nuclear
  transcription factors.
• Transcription of genes important for cell
  proliferation.

RAS
GTP
14-3-3
RAF
SOS
MEK
MAPK
Substrates
41
Metabolic Pathways

• What is metabolism?
• The sum of all the chemical and physical changes
  that take place within the body and enable its
  continued growth and functioning. Metabolism
  involves the breakdown of complex organic
  constituents of the body with the liberation of
  energy, which is required for other processes,
  and the building up of complex substances, which
  form the material of the tissues and organs.

42
Chemical reactions

• Reactants and products
• together called metabolites
• Free energy change (?G) of a reaction
• A B ? C D
• ?G ?Go RT ln CD / AB
• depends on concentrations and nature of
  metabolites
• ?G lt 0 for a spontaneous (exergonic) reaction
• ?G gt 0 for an endergonic reaction
• Chemical equilibrium
• Same rate of forward and backward reactions
• ?G 0, let Keq CD/AB, the ratio of
  products to reactants at equilibrium
• ?Go - RT ln Keq
• Keq e?Go/RT

43
Rate Law

• Consider a reaction of overall stoichiometry,
• The rate, or velocity, v of this reaction is the
  amount of P formed or the amount of A consumed
  per unit time. Thus
• Rate law states that
• Where k is rate constant. v is a function of A
  to the first power, or the first order. k is
  called first order constant.

 
44
Equilibrium constant and equation rates

• For a reversible reaction A B ? C D
• the rate will be the difference between the
  forward and reverse rates
• dC/dt kf AB - kr C D
• At equilibrium,
• kf AB kr C D
• Keq kf / kr C D / AB

45
Enzymes

• usually proteins. A small number of enzymes are
  made of RNA (ribozymes).

• are usually quite big (compared to the portions
  of the reactants or substrates which are modified
  in the reaction to be catalyzed).

Ribozyme (self-splicing intron)
Enzyme(hexokinase)
46
Enzymes have a substrate binding site which
binds the reaction substrates and brings them
together in the orientations appropriate for the
reaction.
This binding is usually highly specific. Often,
one enzyme catalyses only one type of reaction
between a specific set of substrates.
47
Enzymes have an active sitea specialized
configuration of side-chain and main-chain atoms
located at the substrate binding site which
assist in the chemical steps of the reaction.
Active site
Triosephosphateisomerase
48
Active sites

• 3-dimensional cleft
• can be formed by faraway residues
• Lysozymes active site includes residues at
  positions 35, 52, 62, 63, 101, 108 (out of a
  total of 129 residues)
• Small fraction of the total volume of an enzyme
• Substrates are bound to enzymes through multiple
  weak attractions

49
Regulation of enzymes

• Reversible and irreversible inhibition
• Competitive and allosteric regulation
• Allosteric regulation can be activation or
  inhibition
• Tense (T) and relaxed (R) states
• Activator binds to R state
• Inhibitor binds to T state
• Different kinetics for each

50
Rate of reactions
51
Regulatory control of enzymes

• Alteration of enzyme activity
• Enzyme modification
• Covalent modification
• Protein-protein interaction
• Substrate control
• Product control
• Allosteric control

52
Regulatory control of enzymes

• Alteration of number of enzyme molecules
• Transcription
• Translation
• Control of enzyme degradation
• Compartmentalization
• Example hexokinase in brain and liver

53
Enzyme Nomenclature

• Oxidoreductases (EC Class 1)
• Transfer electrons (RedOx reactions)\
• Transferases (EC Class 2)
• Transfer functional groups between molecules
• Hydrolases (EC Class 3)
• Break bonds by adding H2O
• Lyases (EC Class 4)
• Elimination reactions to form double bonds
• Isomerases (EC Class 5)
• Intramolecular rearangements
• Ligases (EC Class 6)
• Join molecules with new bonds

54
Example entry from the Enzyme Database at
http//www.expasy.ch/enzyme/
ID 2.3.1.43 DE Phosphatidylcholine--sterol
O-acyltransferase. AN Lecithin--cholesterol
acyltransferase. AN LCAT. AN
Phospholipid--cholesterol acyltransferase. CA
Phosphatidylcholine sterol sterol ester CA
1-acylglycerophosphocholine. CC -!- Palmitoyl,
oleoyl, and linoleoyl can be transferred a
number of CC sterols, including
cholesterol, can act as acceptor. CC -!- The
bacterial enzyme also catalyses the reactions of
EC 3.1.1.4 and CC EC 3.1.1.5. DI Norum
disease MIM245900. DI Fish-eye disease
MIM136120. PR PROSITE PDOC00110 DR BRENDA
2.3.1.43. DR EMP/PUMA 2.3.1.43. DR WIT
2.3.1.43. DR KYOTO UNIVERSITY LIGAND CHEMICAL
DATABASE 2.3.1.43. DR P10480, GCAT_AERHY
P53760, LCAT_CHICK P04180, LCAT_HUMAN DR
P16301, LCAT_MOUSE Q08758, LCAT_PAPAN P30930,
LCAT_PIG DR P53761, LCAT_RABIT P18424,
LCAT_RAT //
55
Enzyme Catalytic Mechanisms

• Fundamentally familiar reactions from Organic
  Chemistry
• Acid Base Catalysis - Donation or abstraction of
  protons
• Covalent Catalysis - Covalent (co)enzyme-substrate
  intermediate
• Metal Ion - Substrates and metals positioned for
  reaction
• Electrostatic - Charge complimentarity to
  transition state
• Proximity and Orientation - Substrates aligned
  for reaction
• Transition state stabilization - ?G reduced

56
Metabolic networks

• Each enzyme/reaction can be a path between nodes
• Each node is an enzyme substrate (product or
  reactant)
• Converting individual reactions to paths and
  nodes
• Produces directed graphs
• Classification of biochemical reactions
• EC numbering system (Enzyme Commission)
• Hierarchical numerical system i.e. 1.5.3.1
• Based on organic chemistry involved, not proteins

57
Painthe Boehringer-Mannheim wallcharts
58
more pain
59
A Pathway Example
60
Gene Regulatory Networks

• What is gene regulation?
• The primary role of a gene, is transcription,
  which produces mRNA, a copy of a single strand of
  the gene. Different proteins can control the
  transcription process by activating, inhibiting,
  or competitively binding to the promoter region
  of genes.

61
Protein Synthesis

• Transcription
• Before the synthesis of a protein begins, the
  corresponding RNA molecule is produced by RNA
  transcription. One strand of the DNA double helix
  is used as a template by the RNA polymerase to
  synthesize a messenger RNA (mRNA).
• This mRNA migrates from the nucleus to the
  cytoplasm. During this step, mRNA goes through
  different types of maturation including one
  called splicing when the non-coding sequences are
  eliminated. The coding mRNA sequence can be
  described as a unit of three nucleotides called a
  codon.

62
Protein Synthesis

• Translation
• The ribosome binds to the mRNA at the start codon
  that is recognized only by the initiator tRNA.
• The ribosome proceeds to the elongation phase of
  protein synthesis. During this stage, complexes,
  composed of an amino acid linked to tRNA,
  sequentially bind to the appropriate codon in
  mRNA by forming complementary base pairs with the
  tRNA anticodon.
• The ribosome moves from codon to codon along the
  mRNA. Amino acids are added one by one,
  translated into polypeptidic sequences dictated
  by DNA and represented by mRNA.
• At the end, a release factor binds to the stop
  codon, terminating translation and releasing the
  complete polypeptide from the ribosome.

63
Control of Gene Expression

• Gene Expression is a term indicating the act of
  protein synthesis by a gene
• not all genes produce proteins in all cells or in
  all phases of a cells life cycle
• Many control points
• transcription, mRNA processing, nRNA transport,
  translation, post-translational modifications
• Each gene has its own control regions
• all genes differ slightly in the exact locations
  of control and the exact set of transcription
  factors (proteins that control transcription)
• Different combinations of transcription factors,
  and their relative timing of bindings create a
  large space of control signals
• some control signals may control the
  transcription of more than one gene

64
Transcription Regulation
65
Transcription-Initiation Complex
66
Events Leading to Transcription Initiation
67
Enhancers can be equally complex
68
A sense of the data the molecular neighborhood
of IME1
69
Types of Interactions
70
Ontologies and Databases for Biological Pathways
71
BioPax
Database Exchange Formats
Simulation Model Exchange Formats
BioPAX
Small Molecules (CML)
SBML, CellML
PSI
Molecular Interactions ProPro
AllAll
Biochemical Reactions
Genetic Interactions
Rate Formulas
Metabolic Pathways Qualitative
Quantitative
Interaction Networks Molecular
Non-molecular ProPro TFGene
Genetic
Regulatory Pathways Qualitative
Quantitative
Enzymes
72
Design Goals

• Encapsulation An entire pathway in one record
• Compatible Use existing standards wherever
  possible
• Computable From file reading to logical
  inference
• OWL (Ontology Web Language)
• Fast
• Complete all conclusions are guaranteed to be
  computed
• Decidable all computations will finish in finite
  time (with OWL Lite, short amount of time.

73
Requirements Specification

• Accommodate existing database representations
  BioCyc, BIND, WIT, aMAZE, KEGG, etc.
• Compatible as a superset of representations
• Support different pathway types
• Metabolic pathways
• Signaling pathways
• Protein-protein interactions
• Gene regulatory pathways
• OWL- used for encoding the ontology

74
Implementation of BioPAX

• Implemented using OWL language
• OWL is
• Ontology Web Language
• XML based
• W3C standard www.W3C.org
• Example of a BioPAX Class and Instance in OWL

75
Example Class def in OWL
ltowlClass rdfID"protein"gt
ltrdfssubClassOfgt ltowlClass
rdfabout"physicalEntity"/gt
lt/rdfssubClassOfgt ltrdfscomment
rdfdatatype"http//www.w3.org/2001/XMLSchemas
tring"gt A protein (e.g. The EGFR protein
sequence. See Swiss-Prot for more examples.)
lt/rdfscommentgt lt/owlClassgt
76
Example Instance in OWL
ltbpxprotein rdfID"biopax-L1v0.5_Instance_42"gt
ltbpxNAMESgt ltbpxnamesType
rdfID"biopax-L1v0.5_Instance_43"gt
ltbpxSHORTLABELgtphosphoglucose isomeraselt/bpxSHOR
TLABELgt lt/bpxnamesTypegt lt/bpxNAMESgt
lt/bpxproteingt
77
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78
BioPAX Ontology

• Current structure of
• class hierarchy
• Level 1 v0.9 (Dec. 2003)

79
Annotation with BioPax
80
Metabolic Data in BioPAX
EcoCyc Reaction
BioPAX Biochemical Reaction
81
Metabolic Data in BioPAX
EcoCyc Enzyme-Catalyzed Reaction
BioPAX Catalysis
82
Metabolic Data in BioPAX
EcoCyc Pathway
BioPAX Class Pathway
83
Signal Transduction Data in BioPAX
CSNDB Signaling Pathway Step
84
Signal Transduction Data in BioPAX
CSNDB Pathway
85
Descriptions of some databases

• Name KEGG (Kyoto Encyclopedia of Genes and
  Genomes)
• Web http//www.genome.ad.jp/kegg/
• Owner Institute for Chemical Research, Kyoto
  University
• Description KEGG is an effort to computerize
  current knowledge of molecular and cellular
  biology in terms of the information pathways that
  consist of interacting molecules or genes and
  to provide links from the gene catalogs
  produced by genome sequencing projects. The KEGG
  project is undertaken in the Bioinformatics
  Center, Institute for Chemical Research, Kyoto
  Univ.
• Name PathDB
• Web http//www.ncgr.org/pathdb/index.html
• Owner National Center for Genomic Resources
• Description PathDB is a functional prototype
  research tool for biochemistry and functional
  genomics. One of the key underlying philosophies
  of their project is to capture discrete
  metabolic steps. This allows them to build tools
  to construct metabolic networks de novo from a
  set of defined steps. PathDB is not simply a data
  repository but a system around which tools can be
  created for building, visualizing, and comparing
  metabolic networks.

86
List of Pathway Database/Tools (cont.)

• Name GenMAPP (Gene MicroArray Pathway Profiler)
• Gladstone Institute, UCSF.
• GenMAPP is a computer application designed to
  visualize gene expression data on maps
  representing biological pathways and groupings of
  genes. The first release of GenMAPP 1.0 beta is
  available with over 50 mouse and human pathways.
  They also provide hundreds of functional
  groupings of genes derived from the Gene Ontology
  Project for the human, mouse, Drosophila, C.
  elegans, and yeast genomes. GenMAPP seeks
  collaborators in the biological community to
  assist in the development of a library of
  pathways that will encompass all known genes in
  the major model organisms.
•  
• Name SPAD Signaling PAthway Database
• Graduate School of Genetic Resources Technology.
  Kyushu University.
• There are multiple signal transduction pathways
  cascade of information from plasma membrane to
  nucleus in response to an extracellular stimulus
  in living organisms. Extracellular signal
  molecule binds specific intracellular receptor,
  and initiates the signaling pathway. Now, there
  is a large amount of information about the
  signaling pathways which control the gene
  expression and cellular proliferation. They have
  developed an integrated database SPAD to
  understand the overview of signaling
  transduction. SPAD is divided to four categories
  based on extracellular signal molecules (Growth
  factor, Cytokine, and Hormone) that initiate the
  intracellular signaling pathway. SPAD is compiled
  in order to describe information on interaction
  between protein and protein, protein and DNA as
  well as information on sequences of DNA and
  proteins.

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Specific Pathway Databases

• Cytokine Signaling Pathway DB. Dept. of
  Biochemistry. Kumamoto Univ.
• The Database contains information on signaling
  pathways of cytokines. It is designed for
  researchers who work with cytokines and their
  receptors, and provides biochemical data and
  references about signaling molecules as well as
  ligand-receptor relationships.
• EcoCyc and MetaCyc Stanford Research Institute
• EcoCyc database describes the genome and the
  biochemical machinery of E. coli. The database
  contains up-to-date annotations of all E. coli
  genes. EcoCyc describes all known pathways of E.
  coli small-molecule metabolism. Each pathway and
  its component reactions and enzymes are annotated
  in rich detail, with extensive references to the
  biomedical literature. The Pathway Tools software
  provides query and visualization services.
• BIND (Biomolecular Interaction Network
  Database) UBC, Univ. of Toronto
• -- BIND is a database designed to store full
  descriptions of interactions, molecular complexes
  and pathways, including interactions between any
  two molecules composed of proteins, nucleic
  acids and small molecules. Chemical reactions,
  photochemical activation and conformational
  changes can also be described. Abstraction is
  made in such a way that graph theory methods may
  be applied for data mining. The database can be
  used to study networks of interactions, to map
  pathways across taxonomic branches and to
  generate information for kinetic simulations.

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Objectives of the KEGG Project

• Pathway Database Computerize current knowledge
  of molecular and cellular biology in terms of the
  pathway of interacting molecules or genes.
• generic metabolic pathways (143)
• inferred pathways for all sequenced genomes
  (2706)
• Genes Database Maintain gene catalogs of all
  sequenced organisms and link each gene product to
  a pathway component
• Ligand Database Organize a database of all
  chemical compounds in living cells and link each
  compound to a pathway component
• Pathway Tools Develop new bioinformatics
  technologies for functional genomics, such as
  pathway comparison, pathway reconstruction, and
  pathway design

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Data Representation in KEGG

• Entity a molecule or a gene
• Binary relation a relation between two entities
• Network a graph formed from a set of related
  entities
• Pathway metabolic pathway or regulatory pathway

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KEGG Model
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KEGG query capabilities

• Searching an browsing
• Clickable maps
• Map coloring
• user provides a family of genes from gene
  expression data
• matching pathways are listed
• genes are colored on pathway maps
• Path finding between compounds

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Pathway models
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Concluding remarks

• We focused on what needs to be represented
• New kinds of queries
• Graph queries
• Comparison of models and traces
• is flux q possible in steady state for network N?
• Similarity of networks based on the similarity of
  their flux cones
• Compare networks based on
• Their structure
• Their flux cone
• Their dynamic behavior
• What-if queries
• We did not cover logics for simulation
• linear logic, computation tree logic