Metabolism Basics

Two faces of metabolism

• Catabolism - degradation

• Anabolism - biosynthesis

Catabolism• Catabolic sequences yield energy

– ATP, NADH

• Oxidative Oxidizablesubstrate (glucose)

Oxidizedproduct (CO2)

NAD+ NADH

H2O O2ATP

Catabolic Pathways

• Glycolysis• TCA (Krebs) cycle -oxidation of fatty acids• Oxidation of -keto acids

(from amino acids)• Hexose monophosphate

path• Oxidative

phosphorylation• Photophosphorylation

ATP, NADH

GTP, NADH, FADH2

NADH, FADH2

NADH, FADH2

NADPH

ATP

ATP, NADPH

Catabolism is ConvergentCarbohydrates Fats Proteins

Acetyl-CoA

Krebscycle

NADH,FADH2

O2

ATP

Catabolic Regulation

• Allosteric• Covalent

• Hormonal

• Altered gene expression

ATP and PFK-1

Phosphorylation of glycogen phosphorylase

Epinephrine

[cAMP]

Protein phosphorylation

AA oxidizing enzymes

Localization of Catabolism

• Mitochondria (matrix, membrane) -oxidation

– AA oxidation

– Pyruvate oxidation

– Oxidative phosphorylation

Localization of Catabolism

• Cytosol

–Glycolysis

–Hexose-P

• Chloroplast

–Photophosphorylation

Compartmentation of Catabolism

Cytosol Mito

Fatty acids

ATPADP

CoASH CoASH

NADHNADH

Separate pools

Tissue Specialization in Catabolism

• Glycolysis• Krebs Cycle

• Fatty acid oxidation

• Urea cycle-keto acid oxidation

Every CellAlmost every cell

(not RBC)Most tissues (not

brain)LiverLiver (except

branched chains)

Irreversibility of Catabolism

ExergonicGlucose CO2 + H2O -2840 kJ/mol

38 (ADP+Pi) 38 ATP +1160 kJ/mol

∆Go

Irreversible Keq = e-∆Go /RT

= e670

=Very large!

Overall: -1680 kJ/mol

'

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Summary: Catabolism• Oxidative• Convergent• Tightly regulated• Localized intracellularly

– Separate pools• Tissue-specific• Universal• “Irreversible”

– Exergonic

Anabolism (Biosynthesis)• Reductive

• Cofactor: usually NADPH– Pentose-P pathway

– Glutamate dehydrogenase

– Photosynthetic electron transfer

– NADH + NADP+ NAD+ + NADPH

CO2 + [H] CHO

H3C CO

OCH2 CH2

Transhydrogenase

Anabolism: Divergent

Acetyl-CoA

Fatty acids

Eicosanoids

Phospholipids

Triglycerides

Isopentenyl-PP

Vit A

Vit D CoQ

Dolichols

Cholesterol

Bileacids

Estradiol Aldosterone

Cortisol

Anabolism: RegulationGlutamate

Glutamine

Tryptophan

Histidine

CTP AMP

Glucosamine

Carbamyl-P

Complex"Feedback" Inhibition

Anabolism: Localization in Cells• Gluconeogenesis• Fatty acid

synthesis

• Glycogen synthesis

• Starch synthesis• Amino acid

synthesis

Cytosol (mainly)

Cytosol

(Chloroplasts)

Cytosol

Chloroplast

Cytosol

Distinct pools:

In mitos: [NAD+]/[NADH] high

In cytosol: [NADPH]/[NADP+] high

Anabolism: Tissue-Specific

• Gluconeogenesis

• Fatty acid synthesis

• Steroid hormones

• Glycogen synthesis

• Vitamins

Liver (kidney)

Liver, mammary gland

Adrenal cortex, ovaries, testes

Muscle, liverNo tissue; thus

required in diet

Anabolism: “Irreversible”

+ HCO3– CH3C

O

CoAS ATP

ADP + Pi

–30.5 kJ/mol

OC

OCH2 C

O

SCoAMalonyl-CoA

ATP hydrolysis shifts the equilibrium towards the product

Two Separate PathwaysCatabolic path Anabolic path

Reciprocal Regulation

• Anabolic and catabolic pathways are reciprocally regulated

• Regulation occurs at reactions unique to the path

• Same regulator has opposite effect on path– Epinephrine

• Stimulates -oxidation• Inhibits fatty acid synthesis

Summary: Anabolism

• Reductive (NADPH)

• Divergent

• Regulated– At branch points– Reciprocally with catabolism

• Localized– Generally in the cytosol

Summary: Anabolism

• Tissue-specific

–Liver

• “Irreversible”

–Use of ATP

• Separate path from catabolism