Lee metbolic eng synthetic bio BME 162 GuestLecture Apr2_2012

Lee metbolic eng synthetic bio BME 162 GuestLecture Apr2_2012

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Unformatted text preview: 1.8 R3 1.8 R4 R5 R6 R7 − 1.2 − 1.2 − 1.2 0 1.8 0 1.8 − 1.2 − 1.2 − 1.2 0 1.8 1.8 0 − 1.2 − 1.2 − 1.2 − 1.2 − 1.2 − 1.2 0 1.8 1.8 0 0 − 1.2 − 1.2 − 1.2 1.8 0 1.8 0 − 1.2 − 1.2 − 1.2 0 0 0 1.8 0 1.8 0 0 0 0 0 0 0 0 0 0 0 0 R8 Ⱥ 0 Ⱥ Ⱥ 0 Ⱥ Ⱥ 0 Ⱥ 0 Ⱥ Ⱥ 0 Ⱥ 0 Ⱥ Ⱥ 0 Ⱥ 0 Ⱥ Ⱥ s = " !1 !1 !1 1 1 1 !1 !1 $ # % •  Modularity score Q is a func0on of binary vector s; each element si has a value of either  ­1 or 1 •  Vector s maximizing Q approximated by leading eigenvector of G 4/2/12 BME 162 Guest Lecture 55 Algorithm Flow: Itera0ve Binary Par00oning Network graph Find connected subnetworks For each subnetwork: Calculate: ShReD matrix ShReD-based modularity matrix G Leading eigenvector s of G Modularity score Q Check: Number of cycles > 0 for the subnetwork, and Q > 0, and Eigenvector s has at least one positive and one negative element Pass? No Do not partition the subnetwork Yes Partition subnetwork based on the signs of the elements of s Check for both partitions: Number of cycles > 0 Pass? No Do not partition the subnetwork Yes Accept both partitions 4/2/12 BME 162 Guest Lecture 56 ShReD ­Based Par00on of Example Network R8 R4 R2 R1 R8 R3 R7 R5 R6 R7 R4 R5 R2 R6 R1 R3 R2 R8 R1 4/2/12 R7 R3 BME 162 Guest Lecture 57 Par00on of EGFR Signaling Network 4/2/12 BME 162 Guest Lecture 58 Par00on of Liver Metabolic Network 4/2/12 BME 162 Guest Lecture 59 Cofactor Modules •  Cofactor – accepts or donates electron pairs to main reactants; provides reduc0on or oxida0on poten0al A B •  Lec: TCA cycle reac0ons coupled to oxida0ve phosphoryla0on; also coupled to glutamate metabolism, not as intui0ve. •  Right: Lipid metabolism and drug transforma0on coupled through produc0on and consump0on of the cofactor NADPH. •  Apparently unrelated func0ons of lipid synthesis and xenobio0c transforma0on could influence each other depending on the metabolic state of the cell. 4/2/12 BME 162 Guest Lecture 60 Curvature of Metabolic Landscape •  •  4/2/12 Dots show reactions in the redox module Conventional 2D atlas does not show cofactor-mediated coupling BME 162 Guest Lecture 61 Modularity can be implemented biophysically Polyketide Synthase •  AT: acyltransferase •  KS: β-ketoacyl carrier protein synthase •  ACP: acyl carrier protein •  Reductive active sites: β-ketoreductase (KR), dehydratase (DH), enoyl reductase (ER) Lau et al. Biochemistry. 1999 Feb 2;38(5):1643-51. 4/2/12 Dueber et al. Nat Biotechnol. 2009 Aug;27(8):753-9. BME 162 Guest Lecture 62 Programming Cell Behavio...
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