Chapter 15 Metabolism: Basic concepts and design

Part :Ⅰ

the specificity and catalytic power of enzymes

the regulation of enzyme activity

the transport of molecules and ions across membranes

Part :Ⅱ to extract energy and reducing power from its environment

to synthesize the building blocks of its macromolecules and

then the macromolecules themselves

Metabolism: a highly integrated network of chemical reactions

contain many common motifs

Cells transform different types of energy

¤ Phototrophs (photsynthetic organisms):

light energy chemical energy

¤ Chemotrophs:

Utilize chemical energy generated by phototrophs

ion gradient: other types of chemical energy, nerve impulses, etc.

mechanical energy: muscle contraction and movement

synthesis biomolecules

§ 15.1 Metabolism is composed of many coupled, interconnecting reactions

Metabolism(or intermediary metabolism)

Energy is being extracted from fuels via a linked series chemical reactions and used it to power biosynthesis processes

Two broad classes:

¤ Catabolism: fuels transform into cellular energy

Fuels (carbohydrates, fats, etc) CO2+H2O+useful energy

¤ Anabolism:

cellular energy to generate complex structures or energy-rich compounds

Useful energy + small molecules complex molecules

* Amphibolic pathways:

either anabolic or catabolic is depended on the energy conditions in the

cell.

Biosynthetic and degradative pathways are always distinct.

Metabolic pathways – many coupled, interconnecting reactions

§ 15.2 Adenosine triphosphate (ATP) – the universal currency of free energy in biological systems

(XTP?)

2 Phosphoanhydride bonds

Mg2+ or Mn2+

-4 -3

-2

Carbohydrates and fats ATP

Pi: orthophosphate

PPi: pyrophosphate

ATP ADP (ATP-ADP cycle)

the fundamental mode of energy exchange in biological systems

ATP + NDP ADP + NTP (nucleoside diphosphate kinase)

ATP + NMP ADP + NDP (nucleoside monophosphate kinase)

ATP + AMP 2 ADP (adenylate kinase, myokinse)

¤ ATP + H2O ADP + Pi G0’= -7.3 kcal/mol

ATP + H2O AMP + PPi G0’= -10.9 kcal/mol

Under typical cellular condition: G = -12 kcal/mol

A + B C + D

G = G0’ + RT ln [C][D]/[A][B]

¤ A thermodynamically unfavorable reaction can be driven by

a favorable reaction increase a factor of about 108.

Keq of A B under standard condition: 1.15×10-3

Keq of A B under standard condition + ATP: 2.67×102 at pH 7, G°’= -7.3 kcal/mol

Keq of A B under typical cellular condition + ATP : 7.7×105 G= -12 kcal/mol if nATP 108n

¤ ATP hydrolysis drives metabolism by shifting the equilibrium

of coupling reactions

chemical energy coupling agent

protein conformation shift, e.g., muscle contraction

the conc. of ion or molecule on the outside/inside of a cell,

e.g., Na+/K+ pump

What makes ATP a particular efficient phosphoryl-group donor

The free energy of hydrolysis

Three structural factors:

1. resonance stabilization,

2. electrostatic repulsion,

3. stabilization due to hydration

ADP and Pi both effectively bind to water than ATP

squiggle (~P) indication

~ P: high energy bond

Phosphoryl transfer potential – an important form of cellular energy transformation

An efficient carrier of phosphoryl groups

High phosphoryl transfer potential compounds

C

Creatine kinase:

Creatine phosphate + ADP

ATP + creatine

In vertebrate muscle serves as a reservoir of high-potential phosphoryl groups

Sources of ATP (energy) during exercise

Chemotrophs

Phototrophs

immediate energy donor

§ 15.3 The oxidation of carbon fuels

an important source of cellular energy

Free energy of oxidation of single-carbon compounds

H2 11/20 施明哲主任

Two kinds of trapped energy of fuels oxidation

1. A high-energy phosphate compound

GAP 1,3-BPG 3PGA

2. Ion gradient formation

Substrate-level phosphorylation

( p. 443)

acid

Three stages of catabolism

§15.4 Metabolic pathways contain many recurring motifs

¤ Activated carrier of phosphoryl groups, e.g., ATP

¤ Activated carrier of electrons for fuel oxidation

e.g., nicotinamide adenine dinucleotide (NAD+)

flavin adenine dinucleotide (FAD)

¤ Activated carrier of electrons for reductive biosynthesis

e.g., reduced form of nicotinamide adenine dinucleotide phosphate

(NADPH)

NADH is used primarily for the generation of ATP

¤ Activated carrier of two-carbon fragments

e.g., acetyl coenzyme A (CoA)

NAD(P)+: nicotinamide adenine dinucleotide (phosphate)

Niacin (vit. 3)

(Fig. 15.17)

ADP

H+ + 2e-

H- (hydride ion)NADH vs. NADPH

FAD: flavin adenine dinucleotide

isoalloxazine ring

Vit B2 riboflavin

5CFMN

Coenzyme A: a carrier of acyl group

thioester

Transfer acetyl group is exergonic

Acetyl CoA carries an activated acetyl group, just as

ATP carries an activated phosphoryl group.

Two key aspects of metabolism utilize activated carriers:

1. The use of specificity of enzymes to control the flow of free energy and reducing power, such as NAD(P)H, FADH2

2. The economy and elegance of metabolism underlie design

Lys residue

Act as coenzyme:

are needed in small amounts in the diets

at least 12 vitamins are needed

react with hydroxyl radicals

Vitamins: essential to the health of vertebrates but cannot be

synthesized, so must be obtained in the diet.

fat-soluble vitamins: A, D, E, K,

all of which are derived from isoprene units

water-soluble vitamins: C, B, biotin, folic acid, nicotinic acid,…

No biological activity

Nelson

Regulate calcium uptake in the intestine and calcium levels

in the kidney and bone

Vitamin D2 (ergocalciferol): is added to milk and butter

Nelson

Vitamin A (retinol): the visual pigment of the vertebrate eye

β-carotenoids

Cure acne and wrinkled skin

From fish liver oils, liver, eggs, whole milk, butter

carrots, sweet potato, and other yellow vegetables

Deficiency: night blindness, dryness of the skin and eyes…

Nelson

p. 424

Vitamin E:

tocopherols: a substituted aromatic rings and a long isoprenoid

side chain

The aromatic ring reacts with and destroys the reactive oxygen species,

protecting unsaturated fatty acids from oxidation.

Tocopherols: in eggs, vegetable oils, and wheat germ

Vit E deficiency: fragile erythrocytes for humans

scaly skin, muscle weakness and wasting, sterility

Nelson

Vitamin K:

active prothrombin formation

Vit. K deficiency: hemorrhagic disease of the newborn

in U.S.A., newborns are injected Vit. K

Vit. K1 rich in green plant leaves

Vit. K2 is formed by the intestinal bacteria

Nelson

K2: menaquinone

Key reactions are reiterated throughout metabolism

EC1

EC6

EC5

EC2

EC3

EC4

oxidoreductaseligase

isomerase

transferase

hydrolase

lyase

p. 427 can proceed in either direction, depending on G and [reactants]

and [products]

p. 237

15.5

Isomerization

aconitase

Glucose isomerase

The addition of functional groups to double bonds or removal of groups to form double bonds — lyase

aldolase

enolase

The commonalties in the diverse metabolic pathway

(02)

Metabolic processes are regulated in four principal ways

1.The amount of enzymes the rate of synthesis and degradation

the rate of transcription of the genes that encoding enzymes

2. The catalytic activities of enzymes the reversible allosteric inhibition

CTP inhibit asparate transcarbamoylase

the reversible covalent modification

phosphorylation, glycosylation, lipidation, methylation

hormone coordination: epinephrine, insulin

act through 2nd messengers

3. The accessibility of substrates the flux of substrates among different compartments

compartmentalization (synthesis/degradation)

4. The energy state

myristoylation, palmitoylation,prenylation

farnesylation

Ubiquitination: lysis protein

Sumoylation: repress gene expression

small ubiquitin-like modifer, SUMO

KXE

Farnesyl transferase inhibitors are a new class of biologically active anticancer drugs. The exact mechanism of action of this class of agents is, however, currently unknown. The drugs inhibit farnesylation of a wide range of target proteins, including Ras. It is thought that these agents block Ras activation through inhibition of the enzyme farnesyl transferase, ultimately resulting in cell growth arrest.

Energy charge: [ATP] + 0.5 [ADP] / {[ATP] + [ADP] + [AMP]}

catabolism

anabolism

0.9

The pH of a cell

Phosphorylation potential:

[ATP] / [ADP] [Pi] ex. 11

Evolution of metabolic pathways

RNA

ribozymes

96 T

97T

96 C

97C

98T