IMED1003 - Anaerobic Metabolism and Pentose Phosphate Pathway (L14)

Glucose Summary

DIAGRAM ON SLIDE 3

Anaerobic Metabolism

- in the absence of oxygen, fermentation occurs

- In absence of oxygen, NADH accumulates and inhibits pyruvate oxidation

- The pyruvate in turn accumulates and is converted to either lactate or ethanol

- Humans: pyruvate to lactate

- Yeast: pyruvate to ethanol

.

- NADH builds up because oxygen is the terminal electron acceptor in ETC. Remember that NADH, we're making a lot of NADH in glycolysis. Those electrons are carried by NADH to ETC. No oxygen means it can be donated to oxygen

Fermentation of Yeast

- in yeast (and some plants), glucose is converted to ethanol in absence of oxygen

- this fermentation is used in beer and wine production, and bread baking

.

- the goal of the fermentation reaction is to reproduce NAD+

In absence of oxygen, can't undergo TCA cycle, but still need ATP

- hence we need NAD+ for glycolysis

.

- the goal is to reproduce NAD+ (thats the reason its carried out) (goal is to reoxidise NADH)

- lactate is the conjugate base of lactic acid - must be exported

- so if that lactic acid leaves the cell and accumulates in the blood, it lowers blood pH and causes lactic acidosis

Anaerobic Glycolysis

- Objective is not to produce lactate, but to re-oxidise NADH -> NAD+, so can have continued ATP production from glycolysis

- Anaerobic metabolism -> only 2 ATP generated per molecule of glucose (as opposed to 38 ATP with complete oxidation in presence of O2)

- Relatively vast amounts of glucose can be broken down in anaerobic metabolism in very short time

Anaerobic Exercise

- during a sustained sprint, oxygen demand in muscle mitochondria exceeds capacity of blood to deliver it

- For a short time, stored energy (ATP and creatine-P) are used, but this is soon depleted

- Stored glucose and glycogen are burnt via glycolysis, forming lactate, yielding some ATP, but cannot be sustained

- The accumulated lactate must be metabolised (being acidic), which requires oxygen and leads to oxygen debt

- Aerobic training (lower intensity) increases the capacity of blood to carry oxygen. Causes increase in mitochondrial volume and ETC Components

Pyruvate to Lactate

- occurs in cytosol

- Note: symport of lactate and H+ effectively means lactic acid is transported into blood

Cori Cycle

Glycolysis-dependent tissues:

- Skeletal muscle

- Blood cells

- Bone marrow

- Renal medulla

- Peripheral nerves

- Hypoxic Tissues

.

- rescues lactate and keeps blood pH neutral

- muscle exports lactate, liver imports it

- lactate dehydrogenase converts lactate into pyruvate

- gluconeogenesis (requires ATP), converts pyruvate into glucose

- glucose is transported from liver to glucose dependent tissue

Clinical Implications

Hypoxia (not enough oxygen):

- Inhibition of ETC --> decrease ATP --> anaerobic glycolysis

- Glycogen depleted and lactate increased

.

Ischaemia and Myocardial Infarction (ACS) (restriction in blood supply, different to hypoxia)

- As above decreased blood flow --> decreased removal of metabolites (since we have restrictied blood flow) -> decreased energy production -> decreased ion pump function, --> increased intra osmotic pressure

- results in cell swelling and rupture

.

Lactic Acidosis:

- Lactate to CO2 + H2O, or lactate to glucose requires O2

- elevated blood lactate >5mM, decreased blood pH

SUMMARY SO FAR

DIAGRAM ON SLIDE 12

Pentose Phosphate Pathway

Versatile Pathway that does NOT make ATP, but does:

- produce ribose-5P for nucleotide synthesis

- supply NADPH for reductive biosynthesis

- provide pathway for metabolism of excess pentoses

.

- Has oxidative section - get ribose-5P and NADPH and non-oxidative section - manipulation of ribose-5P, depending on cell's needs

- if the cell needs amounts of ribose-5P and NADPH, oxidative PPP proceeds

- If the cell needs lots of NADPH, but not ribose-5P (e.g RBC), then nonoxidative PPP converts excess ribose-5P to glucose-6P to provide substrate for oxidative PPP, hence more NADPH is produced

Pentose Phosphate Pathway Parts

- from intermediates of glycolysis

- reactions are complex - do not need to know details, only enzyme to remember is glucose-6P dehydrogenase (G6PDH)

- G6PDH is the rate limiting one

- enzyme activated by high levels of NADP+

- with high levels of NADP+, glucose is shuttled into PPP rather then glycolysis

- Glucose-6P is an intermediate in glycolysis

- high levels of NADP signals that we need to make more NADPH, so this metabolite feeds into the PPP to serve that requirement

Pentose Phosphate Pathway Products

PRODUCES:

- NADPH = important biological reducing agent (e.g fatty acid biosynthesis)

- NADPH is used to maintain reduced glutathione (GSH), particularly important in RBC

Role of Glutathione in cell

- if we have a situation of oxidative stress, we want a big pool of reduced glutathione to deal with that

- red blood cells are exposed to a lot of oxygen

- we want to make sure they are well equipped to deal with that oxygen in case we get some superoxide radicals being formed (reactive oxygen species)

Clinical Perspective

- Glucose 6 Phosphate dehydrogenase (G6PDH) catalyses first step of Pentose Phosphate Pathway

- G6PDH deficiency leads to haemolytic anaemia

- hereditary and drug induced (anti-malarials, antipyretics, sulphur antibiotics)

- decreased G6PDH -> RBC membrane fragility -> haemolysis

Aerobic Metabolites can

cause damage to cells

Pentose Phosphate Pathway OVERALL

DIAGRAM ON SLIDE 19