Metabolism

- The overall process by which living systems acquire and utilize free energy tocarry out biological work

- The process by which a variety of small molecules are assembled from a fewprecursors; the small molecules then serve as building blocks for macromolecular structures

-Metabolism can be organized into pathways: these pathways may overlap,and branch, and even consist of circular paths

- A pathway consists of consecutive enzymatic reactions: the reactants, intermediates and products are called metabolites

- The flux through each pathway is regulated by a sophisticated set ofmetabolic regulatory mechanisms: feedback inhibition, allosteric interactions,covalent modification of proteins/enzymes, etc.

- Over a 40 year time span a human being consumes tons of nutrients and imbibes 20,000 liters of water, yet remains more or less at steady state

-Metabolic pathways are irreversible at certain key steps where a large negative free energy change occurs

-There are catabolic pathways (e.g.glycolysis) and anabolic pathways (e.g. gluconeogenesis);these are necessarily different at key steps, but may share some steps

-In eukaryotic cells the various metabolic pathways are compartmentalized:cytosol, mitochondria, peroxisomes, chloroplasts, etc.

-The compartments are defined by membranes; special transport mechanisms mustexist to regulate the flow of reactants and products in and out of a compartment

-In some cases the flow is determined by a concentration gradient (diffusion), but stillrestricted by a specific transporter;in other cases integral membrane proteins can act as pumps to pump metabolites and ions against a concentration gradient; this requires an input of energy

Why study metabolism and its regulation?

1. This is what scientists do: it is an intellectual challengeThe final result is satisfying and even beautiful (although beauty is in the eye ofthe beholder)

2. It turns out to have enormous practical value

in the maintenance of our good healtha) a common sense approach to nutritionb) an intelligent response to false advertising

in understanding “metabolic diseases” (inborn errors of metabolism)

a) diagnosisb) possible treatmentsc) establishing a genetic basisd) genetic counselling and prenatal diagnosis

3. you can make a lot of money (drugs, inhibitors, etc.)

http://images.google.com/imgres?imgurl=http://www.momrp.org/images/homepage/bioenergetics_metabolism.gif&imgrefurl=http://www.momrp.org/02.htm&h=170&w=157&sz=8&tbnid=szdr3NVDtxgJ:&tbnh=93&tbnw=86&start=139&prev=/images%3Fq%3Dmetabolism%26start%3D120%26hl%25

POWER = WORK / TIME (Physics)

TIME = MONEY (Business)

KNOWLEDGE = POWER (Academia)

WORKKNOWLEDGE = ______________ (1)

MONEY

Solving for money:

WORKMONEY = _________________

KNOWLEDGE

If the true essence of life is the accumulation of experience through generations, then one may perhaps suspect that the key problem in biology from the physicists point of view is how living matter manages to record and perpetuate the experience

Max Delbruck

Mitchell’s CHEMIOSMOTIC HYPOTHESIS is one of the giant achievements of 20th century science

It can almost literally explain how solar energy can be converted into force and kinetic energy (e.g. muscular motion)or electrical signalling between the brain and our peripheral nervous system

KrebsCycle

UreaCycle

GlyoxylateCycle

CalvinCycle

Acetyl-CoA

Fattyacids

Glucose

Glycogen

PEP

mevalonate

Cholesteroletc.

CO2

CO2

Light Reactions

Electron TransportOXPHOS

KEGG

Kyoto Encyclopedia of Genes and Genomes

OMIMOnline Mendelian Inheritance in Man

glycolysis

glucokinase

phosphofructokinasePFK-1

pyruvate kinase

gluconeogenesis

phosphatase

phosphatase

PEP carboxykinase

pyruvate carboxylase

2 ATPs produced4 ATP, 2 GTP, 2 NADH needed

LIVERMUSCLE

-oxidation of fatty acids:

1. Activation in cytosol toacyl-CoA

2. Transacylation to formacyl-carnitine

3. Import into mitochondria

4. Transacylation to acyl-CoA

5. Four steps in -oxidation

1. in plants

2. long chain FA in animal cells

Ketone bodies

lyase

decarboxylase

dehydrogenase

acetyl-CoA+

acetoacetate

acetone-hydroxy-butyrate

Oxidative phosphorylation in mitochondria

[2Fe-2S] [4Fe-4S]

atractyloside x

xrotenone

xmalonate

xantimycin

xcyanide

Photosynthesis in chloroplasts

5 C3 -P 3 C5 - P

C3 + C3 C6*

C6* C6

C6 + C3 C4 + C5

C4 + C3 C7*

C7* C7

C7 + C3 C5 + C5’

aldolase

aldolase

transketolase

transketolase

phosphatase

phosphatase

Net reaction:

2 glycolate (C2)

1 phospho-glycerate (C3) +

CO2

ATP

ADP

Photorespiration

Raising CO2 concentrations

in

C4 plants

alternate enzyme:

PEP carboxylase

cost:

2 ATP (effectively)

Cholesterol and isoprenoid

synthesis

important target fordrugs to lowercholesterol levels

Several important vitamins converted to cofactors

and their participation in various reactions

BIOTIN IS INVOLVED IN

ACTIVATION OF CO2 IN

CARBOXYLATION REACTIONS

e.g. pyruvate carboxylase

BIOTIN IS INVOLVED IN ACTIVATION OF CO2 IN

CARBOXYLATION REACTIONS

e.g. acetyl-CoA carboxylase

Vitamin B12

(cobalamin)

in pathway of propionyl-CoA utilization

Involvement in decarboxylation reactions, e.g. pyruvate

Trace Metals in Metabolic Biochemistry

Fe electron transport chain; [Fe-S], cytochromes

Cu complex IV (mitochondria), plastocyanin (chloroplasts)

Mn oxygen evolving complex in chloroplasts

Co vitamin B12

Mg, Ca, too numerous to mention