Energy-generating pathway from glycogen

glycogen(from triglycerides)-->glucose--(GLYCOLYSIS)-->pyruvate--> 1 AcCoA (each pyruvate has 3 C, each AcCoA has 2)

Energy-generating pathway from triglycerides

triglycerides(fatty acid + glycerol)--(lipolysis)-->free fatty acid--(beta oxidation)-->8 AcCoA (each fatty acid has 16 C)

with every cleavage (during beta ox), 1 NADH and 1 FADH are formed-->term ox-->ATP

Energy-generating pathway from protein

protein--(proteolysis)-->amino acids-->AcCoA

*Some a.a. produce pyruvate, which is then converted to AcCoA, and some directly enter Krebs cycle

Which generates more energy, glucose or triglycerides?

TRIGLYCERIDES

How AcCoA is converted into E

AcCoA-->Krebs-->Terminal oxidation-->ATP

Carnitine transport system

transports fatty acids into mitochondria for beta oxidation

how amino acids enter energy metabolism

1. enter TCA as intermediates-->term ox-->ATP

2. can be turned into AcCoA-->TCA-->term ox-->ATP

3. converted to pyruvate-->AcCoA etc

sources of pyruvate

glycogen/glucose and some amino acids (ex: alanine)

pyruvate can be converted into (4):

1. AcCoA through oxidative decarboxylation by pyruvate dehydrogenase complex (PDH) under AEROBIC CONDITIONS

2. Lactate by reduction--end product of glycolysis under ANAEROBIC CONDITONS

3. Alanine by transamination (protein synthesis)

4. oxaloacetate by carboxylation (glycolysis)

(5. Ethanol in yeast and bacteria)

PDH complex location

mitochondrial matrix

PDH complex reaction ΔG

very negative-->irreversible

PDH complex composition

'complex'-->quaternary structure (multiple subunits of each enzyme bind together--highly efficient), 3 enzymes, 5 coenzymes, 2 regulatory enzymes

pyruvate carboxylase

glycolytic enzyme that converts pyruvate to oxaloacetate

entry point of TCA cycle

irreversible reaction

PDH enzymes

E1: pyruvate dehydrogenase (decarboxylase)

E2: dihydrolipoyl transacetylase

E3: dihydrolipoyl dehydrogenase

PDH coenzymes

thiamine pyrophosphate (TPP, vit B1)

lipoic acid (vitamin)

coenzyme A (vit B5)

FAD (vit B2)

NAD (vit B3)

PDH rxn

pyruvate + NAD⁺ + CoASH --> AcCoA + CO₂ + NADH + H⁺

NADH and AcCoA -->Krebs

PDH regulatory enzymes

protein kinase

phosphoprotein phosphatase

phosphorylation/dephosphorylation

PDH E1

pyruvate decarboxylase

converts pyruvate into AcCoA precursor + carbon dioxide

requires TPP coenzyme

PDH E3

dihydrolipoyl dehydrogenase oxidizes lipoic acid (which is then added to precursor) by reducing FAD to FADH2

same enzyme reoxidizes FADH2 to FAD and simultaneously reduces NAD to NADH + H+, replenishing FAD that the first half of the rxn depends on

Pyruvate dehydrogenase regulation

1. Feedback inhibition: products (AcCoA, NADH & CO2) inhibits

2. phosphoprotein phosphatase: dephosphorylates-->activates

*regulation of phosphatase: Ca2+ activates

3. Protein kinase: phosphorylates--> inactivates

*reg. of kinase: pyruvate inactivates, ATP/AcCoA/NADH activates

Pyruvate dehydrogenase deficiency

lactic acidosis-->neurological defects and DEATH

Tx: ketogenic diet (avoid glucose)

dichloroacetate (kinase inhibitor--activates enzyme)

fates of AcCoA

TCA cycle, ketone bodies (feed brain during starvation), fatty acid/ sterol synthesis

Krebs location

mitochondrial matrix

Krebs cycle function (2)

1. final common pathway in nutrient catabolism

2. anabolic processes--intermediates facilitate gluconeogenesis, lipogenesis and transamination/deamination of aa **liver is the only tissue where all occur at a significant level

4 dehydrogenases of TCA cycle

I-A-M-S

Isocitrate DH (NADH)

alpha-ketoglutarate DH (NADH)

Succinate DH (FADH2)

Malate DH (NADH)

1 FADH2, 3 NADH produced

substrate-level phsophorylation

produces GTP (equivalent in E to ATP)

E produced in 1 turn of TCA

9 ATP from NADH (3 each)

2 ATP from FADH2 (2 each)

1 GTP

12 ATP/AcCoA oxidized

TCA regulation

inhibitors: NADH, Succinyl CoA, ATP, GTP

activators: Ca2+, ADP

see 242 for points of regulation

regulation of PDH plays major role:

lack of AcCoA, NAD or FAD will also stop TCA

TCA cycle pathology

few genetic abnormalities because TCA is so critical

mutations usually incompatible with life

Arsenic poisoning

affects enzymes using lipoic acid as a cofactor (PDH and alphaketoglutarate DH)

fumarase deficiency

autosomal recessive disorder

severe neuro impairment, encephalomyopathy, dystonia

high levels of fumarate, succinate, alphaketoglutarate and citrate in urine

anabolic function of TCA

intermediates can be channeled into biomolecule synthesis pathways

citrate--fatty acids and sterols

malate--glucose

succinyl coA--heme (dALA synthase coenzyme)

alphaketoglutarate--aa synth-->neurotransmitters

oxaloacetate--non-essential aa

anaplerotic reactions

filling reactions, replenish TCA cycle intermediates which are removed for biosynthetic purposes

most important=pyruvate carboxylase (dehydrogenase)-->oxaloacetate (plus AcCoA)

aa can also serve as a source of 4C intermeds, esp during fasting