comp 150 csb – computational systems biology · }examples: bisphenols(bp) and polychlorinated...

Soha HassounDepartment of Computer Science (primary)Department of Chemical and biological Engineering

Department of Electrical and Computer Engineering

COMP 150 CSB –Computational Systems Biology

Introduction

Example: Artemisinic acid as a viable source of antimalarial drug artemisinin SOURCE: Nature, 2006

Malaria threatens 300-500 millionKills more than one million people

Keasling’s work reduces dose pricefrom $2.40 to $0.25!

Example: Engineering a minimal E. Coli cell to maximize the production of ethanol

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Trinh et al., Applied and

Environmental Microbiology,

June 2008

Biomass

Ethanol

Pentoses

Hexoses

Example: Predicting transformations of POPs by human liver enzymes

} Humans and animals are exposed to Persistent Organic Pollutants (POPs)} Examples: bisphenols (BP) and polychlorinated biphenyls (PCB)} Linked to metabolic disorders (type 2 diabetes and obesity), and

to cardiovascular disease, hypertension, endocrine disruption, and many other disorders

} The human liver has the potential to perform biotransformationson POPs} Active harmful form is not the POP, but its derivative

} Challenge: how to predict transformations by theliver

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Example – Designing and Analyzing Microbial Community} Gut microbiota (consortium of GI tract bacteria)

} 1013 – 1014 bacterial cells (10 times number of human cells)} 70 to 140 times more genes than the human host} Plays important roles in physiological functions

} Digestion, metabolism, immune response} Implicated in many diseases

} Colon cancer, inflammatory bowel disease (IBD), obesity} Challenges

} Analyzing sequencing data on stool DNA can shed light on “who is there”, and “how much”, and “what are they doing”

} Interaction with host

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Example - What Can Metabolomics Do For You?Analysis of the Gut microbiota

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New York Times, 6/23, 2015

Background

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Background

Genes

8

DNA

Genes

Image from Khan academy

Genes encode for specific proteins

Bio Basics: From Gene Regulatory Networks to Metabolic Networks

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DNA

mRNA

Enzyme

A

B

C D

E

F

R1 R2 R3

R4

R5

Gen

etic

Reg

ulat

ory

Net

wor

ksM

etab

olic

Net

wor

kstranscription

using RNA polymerase

translationusing ribosome

enzymes catalyze reactions

transcriptional regulation

feedback

allostericregulation

CONTROL

DATA FLOW

Conceptually: Data Flow vs. Control

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DNA

mRNA

Enzyme

A

B

C D

E

F

R1 R2 R3

R4

R5

Gen

etic

Reg

ulat

ory

Net

wor

ksM

etab

olic

Net

wor

kstranscription

using RNA polymerase

translationusing ribosome

enzymes catalyze reactions

transcriptional regulation

allostericregulation

Metabolism} Metabolism: refers to the entire network of biochemical

processes involved in maintaining life.} Energy metabolism: the ways that the body obtains and

spends energy from food.} Catabolism: The breakdown of molecules into smaller units. Energy

is released in this process. Products of catabolic pathways will be used in further catabolic reactions until molecules are reduced to waste} Ex: Glucose catabolism results in the release of CO2 and H2O and

produces ATP

} Anabolism: The building of compounds from small molecules into larger ones. Chemical energy stored in co-substrates (ATP, NADH, NADPH) is used for this process to take place.} Ex: Amino acids build proteins; sugars build polysaccharides; fatty acids build

lipids; 11

Cellular Metabolism} Cells are the site of metabolic activity

} How many cells does the human body contain?} 1x1014 cells or 100 trillion cells

} Goal – Analyze and manipulate cellular metabolism

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Fundamentals} A metabolic network

} Stoichiometric matrix represents a biochemical network

} Reactions can be reversible: thermodynamics dictate direction

R1 R2 R3 R4 R5

A -2

B -1

C 1 -1 1

D 1 -1 -1

E 3

F 1 -1

A

B

C D

ER1 R2

R3

R5 FR4

Graph representation

reactionreactants

product

Constraint-Based Optimization to Maximize Yield

A

B

C D

ER1 R2

R3

R5 FR4

A

B

C D

ER1 R2

R3

R5 FR4

Possible Flux Distributions whenmaximizing ?

Maximum Flux for = ???

A

B

C D

ER1 R2

R3

R5 FR4

A

B

C D

ER1 R2

R3

R5 FR410

1010

0

0

Possible Flux Distributions for = 10

Maximum Flux for = 10

Constraint-Based Optimization to Maximize Yield

Chemical Reactions vs. Biochemical Reactions

Chemical Reaction

• Biochemical Reactions take place inside cells of living things.

• Most biochemical reactions need help to take place. Help comes from enzymes. Enzymes are specific: they help a specific type of reaction. They need to bind with the right shape molecules to catalyze a reaction. Enzymes can catalyze more than one reaction.

Biochemical Reactions

What affects reaction rates?Assume there is plenty of enzymes to be re-usedReaction rates saturate as a function of substrate concentrationEnzymatic reaction modeled using an equation, named after

German biochemist Leonor Michaelis and Canadian physician Maud Menten. (Michaelis-Menten model)

Vmax

0.5 Vmax

K’M Concentration of Substrate [D]

Rea

ctio

nR

ate v

‘

*

p.s. the real problem is much harder…

What is this class about?} Cover 3 topics

1. Biochem-informatics: molecules, reactions2. Metabolic Networks: Analysis & Synthesis3. Metabolomics

} Regular readings and weekly blogging} 4 homeworks covering Topics 1 & 2} Project based on any of the three topics, but topics 1 & 2

if you don’t have background or interest in topic 3} Research presentation about Topic 3

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