PDH Case

Fermentation of Pyruvate

• pyruvate + NADH + H+ → lactate + NAD+

• Converts pyruvate to lactate, regenerating NAD+ for glycolysis.

• This process occurs in anaerobic conditions and allows for ATP production when oxygen is scarce.

Aerobic Respiration of pyruvate

• when oxygen is readily avaiable it is used as a downstream electron acceptor to help move pyruvate

• enters the mitochondrion and is converted into acetyl-CoA by PDH complex

• Pyruvate → Acetyl-CoA + CO2

• connects glycolysis with the citric acid cycle

Overall goal of PDH

convert pyruvate to acetyl-CoA, release CO2 and produce NADH → help prepare for citric acid cycle

Overall goal of citric acid cycle

oxidizes the acetyl group from actyl-CoA and CO2 and captures energy in NADH/FADH2/GTP and ATP

harvests energy in forms ATP can use

E1

• pyruvate dehydrogenase

• uses TPP to remove CO2 from pyruvate through oxidative decarboxylation

E2

• lipoamide

• transfers the acetyle group to coenzyme A (CoA), forming Acetyl-CoA

• uses lipoamide to carry the intermediate between enzyme active sites

• dihydrolipopyl TRANSacetylase

E3

• regenerates oxidized lipoamide so PDH complex can continue functioning

• FAD

• reduced lipoamide transfers e- to FAD to FADH2, FADH2 transfers e- to NAD+ to NADH

• oxidized lipoamide is regenerated ready for another round

• lipoamide → FAD → NAD+

Stochiometric enzymes

• CoA and NAD+

• enter the rection as substrates and are used to form products

Catalytic enzymes

• TPP, lipoamide, FAD

• participate in the reaction but get regenerated so they can be used again

Where does glycolysis occur

cytosol

Where does PDH complex occur

mitochondrial matrix

Where does citric acid cycle occur

mitochondiral matrix

Where does ETC occur

inner mitochondrial membrane

pyruvate carboxylase

• converts pyruvate into oxaloacetate (OAA)

• uses ATP and CO2 and requires biotin

pyruvate dehydrogenase

• converts pyruvate into acetyl-CoA

• releases CO2 and produces NADH

High energy state → TCA Slow down

• the cell has plenty of ATP and e- carriers → NADH

• doesn’t need to breakdown as much fuel

Low energy state → speed up

• cell needs more ATP

• signals like ADP and NAD+ indicate energy production needs to increase

What INHIBITS PDH

• ATP is high

• NADH is high

• Acetyl-CoA is high

What ACTIVATES PDH

• ADP is high

• NAD+ is available

• CoA is available

Kinase

inhibits

phosphatase

activates

anaplerosis

replenishment of TCA-cycle-intermediates

PDHA1

encodes for E1 subunit

• if mutated E1 activity impairs pyruvate so pyruvate is directed to lactate

Keto diet

• encourages he body to use fat as an energy source

• may help lessen lactate levels

• might not improve neuro symptoms

DCA (Dichloractate)

helps activate PDH by targeting PDH complex

Oral citrate

helps manage acidosis by addressing acid-base consequence of PDH