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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
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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!
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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
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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
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Background
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Background
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Genes
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DNA
Genes
Image from Khan academy
Genes encode for specific proteins
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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
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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
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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
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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
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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 = ???
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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
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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
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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
‘
*
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p.s. the real problem is much harder…
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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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