L12:Oxidation of hydrocarbons, lipids and the glyoxylate cycle

What is the glyoxylate cycle and its metabolic purpose?

A CAC bypass that preserves carbon skeletons by producing malate from isocitrate via isocitrate lyase, bypassing 2 decarboxylation steps that release CO₂

• replenishing CAC intermediates for biosynthesis and allowing for growth on fatty acids instead of carbohydrates.

• enables organisms to convert FAs into carbohydrates, facilitating energy generation and growth in certain microorganisms and plants.

What is involved in β-oxidation?

The process involves the enzymatic breakdown of fatty acids into acetyl-CoA units, accompanied by the production of NADH and FADH₂ for ATP generation.

Main steps in β-oxidation

• Co-enzyme A is used to ‘activate’ the fatty acid

• Oxidation of the carbon-carbon bond between alpha and beta carbon atoms

• FADH formed

• Makes the beta-carbon atom vulnerable to ‘attack’ by water resulting in its oxidation → NADH produced

• Acetyl CoA is split off and the cycle starts again

Beta-oxidation: oxidation of the beta carbon atom of the fatty acid

How does the glyoxylate bypass replace finite CAC intermediates?

• Isocitrate lyase cleaves isocitrate → succinate and glyoxylate

• Glyoxylate condenses with acetyl CoA to form malate.

• Contributes a new CAC intermediate molecule

• Instead of being oxidised to 2 CO2 molecules, the 2-C glyoxylate fragment condenses with another acetyl CoA to form the 4-C compound malate.

Increases levels of all CAC intermediates, because malate can be oxidised to oxaloacetate that condenses with yet another acetyl CoA to form citrate, and so on.

What steps of the CAC are bypassed by the glyoxylate cycle?

The glyoxylate cycle bypasses the decarboxylation steps involving isocitrate DH and alpha-ketoglutarate DH, which release CO2

What enzymes are induced / inhibited by cells growing on acetate / FAs?

Cells growing on acetate or fatty acids induce synthesis of isocitrate lyase (aceA) AND inhibit activity of isocitrate dehydrogenase to force flow of carbon through the glyoxylate bypass

• This allows assimilation via gluconeogenesis of fatty acids and acetate

What is gluconeogenesis?

the process of making glucose from non-carbohydrate sources i.e. CAC intermediates, amino acids, acetate to support energy needs and biosynthesis when sugars are scarce.

Why is the glyoxylate cycle is essential for growth on fatty acids?

Fatty acids yield only acetyl-CoA

β-oxidation produces acetyl-CoA, but acetyl-CoA cannot be converted into glucose through the standard TCA cycle because:

• In the TCA cycle, the two carbons from acetyl-CoA are lost as CO₂

• There is no net carbon gain for biosynthes

How is the glyoxylate cycle important for C skeleton preservation?

The glyoxylate cycle conserves carbon

The glyoxylate cycle bypasses the CO₂-producing steps (isocitrate dehydrogenase and α-ketoglutarate dehydrogenase). This allows:

• Net conversion of acetyl-CoA carbon into succinate and malate

• Preservation of carbon skeletons needed for anabolism i.e. AA biosynthesis

What is a pathogen that uses the glyoxylate cycle for virulence?

Rhodococcus equi causes pneumonia in horses and grows inside host cells

• grows well on both fatty acids and acetate AND induces Isocitrate lyase when growing inside host cells