CBoL - BIOSYNTHETIC PATHWAYS

Anabolic pathways

Fed state

* High levels of plasma glucose, amino acids, and triglycerides

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Control:

* High levels of insulin secretion by pancreas, low levels of secretion of glucagon

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Response: (anabolic)

* Liver - makes glycogen, proteins, triglycerides
* Adipose - makes triglycerides
* Muscle - makes protein

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Glycogen = stored form of glucose - fuel for tissues

Fasting state

* Low levels of plasma glucose, amino acids, and triglycerides

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Control:

* Low levels of insulin secretion by pancreas, High levels of secretion of glucagon and adrenaline

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Response: (catabolic)

* Liver - glycogenolysis, gluconeogenesis, beta-oxidation and ketogenesis (breaks down fat)
* Adipose - lipolysis (breakdown of triglycerides)
* Muscle - uses fatty acids and ketone bodies as fuel
* Brain - uses glucose and ketone bodies as fuel

Gluconeogenesis

* RBC fully dependent on glucose, brain heavily dependent on glucose.
* Glycogen stores last 8-10 hours

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Gluconeogenesis is the process by which glucose is formed from non-carbohydrate precursors (i.e. lactate, glycerol, amino acids.) Some reactions in this process are irreversible.

* requires energy

Glycerol

Glycerol → (Glycerol kinase) → glycerol phosphate

* Glycerol kinase: expressed in liver, kidney, intestine

Acetyl CoA

Can be generated from the breakdown of fatty acids but is not a substrate from gluconeogenesis.

* Pyruvate dehydrogenase reaction is irreversible

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High levels of Acetyl CoA:

* activates pyruvate carboxylase → simulates gluconeogensis → inhibits pyruvate dehydrogenase → inhibits glycolysis

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High levels of AMP:

* inhibits gluconeogenesis → activates glycolysis

Amino acids

Some can be converted to TCA intermediates

Carboxylation of Pyruvate

In Glycolysis: pyruvate kinase

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Bypassed in Gluconeogenesis is bypassed by:

* Pyruvate carboxylase: pyruvate → oxaloacetate
* PEP carboxylase: oxaloacetate → PEPI

Dephosphorylation of fructose-1,6-bisphosphate

In Glycolysis: phosphofructokinase

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In Gluconeogenesis bypassed by:

* Fructose 1,6 bisphosphate

Dephosphorylation of G6P

In Glycolysis: Hexokinse/glucokinase

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In gluconeogenesis bypassed by:

* glucose-6-phosphatatse

Entry points of gluconeogenesis substrates

1. Glycerol → glyceraldehyde 3-P
2. Lactate → pyruvate
3. Amino acids → oxaloacetate

Pentose phosphate pathway

Generates NADPH and 5-carbon sugars

* If glucose is plentiful, a certain amount of glucose-6-phosphate can be used in pentose phosphate pathway instead of glycolysis

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1. Oxidative phase: NADPH production

Irreversible reactions:

* Catalysed by Glucose 6-phosphate dehydrogenase (redox reaction)
* 6-phosphogluconolactone hyrdolase

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2. Cyclical phase: 5-carbon sugars production
* Interconversion of 3,4,5,6,7-carbon sugars

Why is NADPH important?

Functions as a biochemical reductant.

* Some enzymes can only use NADPH as a coenzyme
* Used in fatty acid synthesis
* Used in antioxidant reactions

Regulation of pentose phosphate pathway

* Rate and direction of reversible reactions depend on supply and demand of intermediates.
* Regulated at glucose-6-p dehydrogenase (rate limiting step)
* Insulin increase G6PD gene expression

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Active when glucose is high and plentiful.

G6PD deficiency

* Most common enzyme abnormality


* Inherited X-linked

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* Reduced NADPH in erythrocytes → glutathione not regenerated → oxidative damage
* Effects most severe in RBC as they rely on pentose phosphate pathway for NADPH

G6PD deficiency precipitating factors

* Oxidant drugs: antibiotics
* Favism: ingestion of fava beans
* Infection: most common factor - Inflammatory response = generation of free radicals
* Neonatal jaundice