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Amarnath Gupta

Department of Computer Science & Engineering University of California, San Diego CSE-291: Ontologies in Data Integration Spring 2004 Ontologies and Biological Pathways. Amarnath Gupta. So, What is an Ontology Again?. From previous classes

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Amarnath Gupta

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  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 let’s 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 • Allen’s interval relations 2A. Artale and E. Franconi. “A temporal description logic for reasoning about actions and plans”. Journal of Artificial Intelligence Research, 9:463--506, 1998

  7. Temporal Description Logic • Ingredients • non-temporal concepts E • temporal concepts C • things that change their state • temporal qualifier C@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 Allen’s interval relations or an expression composed from it • existential quantifiers • ⋄ (X) Tc.C • selections p:E where p is • an atomic feature f • a parameterized feature *f

  8. Applying Temporal DL • Translocation of a protein • translocation ≐⋄(xy)(x m #)(# m y) ((*Protein: InCytoplasm)@x⊓ (*Protein: InNucleus)@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)) translocation # in-nucleus(protein) in-cytoplasm(protein) y x

  9. Applying Temporal DL • Some identities • ⋄ x (x a #). C@x ≡ ⋄ xy (y mi #)(x mi y). C@x • ⋄ x (x d #). C@x ≡ ⋄ xy (y s #)(x f y). C@x • ⋄ x (x o #). C@x ≡ ⋄ xy (y s #)(x fi y). C@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@x⊓ autophosphorylation) • GRB2_s_r ≐⋄ (y z w)(y b w)(z b w) (tyrosine_p@y ⊓ PTK_l_b@z ⊓ GRB2_b@w)

  10. Applying Temporal DL • More features of the temporal DL • path p ○ q • *Protein○ bound should be interpreted as • ∃ a,p,i,o1Protein(a, p, i) ⋀ bound(i, p, o1) • Agreement operator ↓ • (*Protein○ bound ↓ *Receptor)@y means at the interval y the object to which Protein is bound is Receptor) • Substitution • Suppose A ≐ ⋄(xy z w)(…) is an axiom and B ≐ ⋄(xu v)(…) is another axiom whose body is a part of A • The temporal substitutive qualifier (B[x]@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-MAPKpathways • 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 P P P P • Ligand binds receptor PTK • Autophosphorylation on tyrosine

  24. RAS-RAF-MEK-MAPK SOS GRB2 SH2 SH3 P P P P • 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 GRB2 SH2 SH3 P P P P • 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 RAS GDP GRB2 SH2 SH3 P P P P • Recruitment of SOS to the close proximity of RAS in the membrane SOS

  27. RAS-RAF-MEK-MAPK GRB2 SH2 SH3 P P P P • RAS becomes activated by exchanging GDP for GTP RAS GTP GDP SOS

  28. RAS-RAF-MEK-MAPK GRB2 SH2 SH3 P P P P • 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 GRB2 SH2 SH3 P P P P • 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 GRB2 SH2 SH3 P P P P • 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 GRB2 SH2 SH3 P P P P P P • 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 GRB2 SH2 SH3 P P P P P P • 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 GRB2 SH2 SH3 P P P P P P P P • 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 GRB2 SH2 SH3 P P P P P P P P • 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 GRB2 SH2 SH3 P P P P P P P P P P • 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 GRB2 SH2 MAPK SH3 P P P P P P P P P P • • 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 GRB2 SH2 MAPK SH3 MAPK P P P P P P P P P P • • 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 GRB2 SH2 MAPK SH3 P P P P P P P P P P • • 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 GRB2 SH2 MAPK SH3 P P P P P P P P P P P • • 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 GRB2 SH2 MAPK SH3 P P P P P P P P P P P • • 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 (ΔG) of a reaction A + B  C + D ΔG = ΔGo+ RT ln [C][D] / [A][B] • depends on concentrations and nature of metabolites • ΔG < 0 for a spontaneous (exergonic) reaction • ΔG > 0 for an endergonic reaction • Chemical equilibrium • Same rate of forward and backward reactions • ΔG = 0, let Keq = [C][D]/[A][B], the ratio of products to reactants at equilibrium • ΔGo = - RT ln Keq • Keq = e–ΔGo/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 [A][B] - kr [C] [D] At equilibrium, kf [A][B] = kr [C] [D] Keq = kf / kr = [C] [D] / [A][B]

  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 sitewhich 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 site—a 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 • Lysozyme’s 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

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