FA Biochem 8 Metabolism

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Glycolysis/ATP production

How much ATP is produced via the different pathways?

Aerobic metabolism of glucose produces 32 ATP via malate-aspartate shuttle (heart and liver), 30 ATP via glycerol-3-phosphate shuttle (muscle)

Anaerobic glycolysis produces only 2 net ATP per glucose molecule.

ATP hydrolysis can be coupled to energetically unfavorable reactions.

Activated carriers (7)

Phosphoryl (ATP)
Electrons (NADH, NADPH, FADH₂)
Acyl (coenzyme A, lipoamide)
CO₂ (biotin)
1-carbon units (tetrahydrofolates)
CH₃ groups (SAM)
Aldehydes (TPP)

Universal electron acceptors

What are they, and what are they used for?

Nicotinamides (NAD⁺, NADP⁺) and flavin nucleotides (FAD⁺)

NAD⁺ is generally used in CATABOLIC processes to carry reducing equivalents away as NADH.

NADPH is used in ANABOLIC processes (steroid and fatty acid synthesis) as a supply of reducing equivalents.

NADPH is a product of the HMP shunt.

NADPH is used in:
1. Anabolic processes
2. Respiratory burst
3. P-450
4. Glutathione reductase

Hexokinase vs. glucokinase

Phosphorylation of glucose to yield glucose-6-phosphate serves as the 1st step of glycolysis (also serves as the first step of glycogen synthesis in the liver).

Reaction is catalyzed by either hexokinase or glucokinase, depending on the location.

Hexokinase

Ubiquitous.

High affinity (low Km), low capacity (low Vmax), uninduced by insulin.

Feedback inhibited by glucose-6-phosphate


Vmax represents the maximum rate achieved by the system

Km is the substrate concentration at which the reaction rate is half of Vmax.

Glucokinase

Liver and β cells of pancreas.

Low affinity (high Km), high capacity (high Vmax), induced by insulin.

No direct feedback inhibition.

Phosphorylates excess glucose (e.g. after a meal) to sequester it in the liver. Allows liver to serve as a blood glucose "buffer."

"GLUcokinase is a GLUtton. It has high Vmax because it cannot be satisfied"

Regulation by F2,6BP

Fructose-6-phosphate → Phosphofructokinase 2 (active in fed state) → Fructose-2,6-bisphosphate → positive feedback → glycolysis

Fructose-2,6-bisphosphate → Fructose bisphosphatase 2 (active in fasting state) → Fructose-6-phosphate → gluconeogenesis

FBPase-2 and PFK-2 are part of the same complex but respond in opposite manner to phosphorylation by protein kinase A.

Fasting state: ↑ glucagon → ↑ cAMP →↑ FBPase-2, ↓ PFK-2

Fed state: ↑ insulin →↓ cAMP →↓ protein kinase A →↓ FBPase-2, ↑ PFK-2

Pyruvate dehydrogenase complex

Reaction, 5 cofactors, activated by what, similar to what other complex

Reaction: pyruvate + NAD⁺ CoA → acetyl-CoA + CO₂ + NADH

This complex contains 3 enzymes that require 5 cofactors:
1. Pyrophosphate (B₁, thiamine; TPP)
2. FAD (B₂, riboflavin)
3. NAD (B₃, niacin)
4. CoA (B₅, pantothenate)
5. Lipoic acid

Activated by exercise:
↑ NAD⁺/NADH ratio
↑ ADP
↑ CA²⁺

This complex is similar to α-ketoglutarate dehydrogenase complex (same cofactors, similar substrate and action), which converts α-ketoglutarate → succinyl-CoA (TCA cycle).

____ inhibits lipoic acid

Findings (3)

Arsenic inhibits lipoic acid.

Findings: vomiting, rice water stools, garlic breath

Pyruvate dehydrogenase deficiency

Causes, findings, treatment

Causes backup of substrate (pyruvate and alanine), resulting in lactic acidosis.

Can be congenital or acquired (as in alcoholics due to B₁ deficiency).

Findings: neurologic defects

Treatment: ↑ intake of ketogenic nutrients (e.g. high fat content or ↑ lysine and leucine)

"Lysine and Leucine - the only purely ketogenic amino acids"

Pyruvate metabolism

4 different pathways

Pyruvate (from glucose)
↔ Alanine
→ Oxaloacetate
→ Acetyl-CoA
↔ Lactate

Functions of different pyruvate metabolic pathways:
1. Alanine carries amino groups to the liver from muscle
2. Oxaloacetate can replenish TCA cycle or be used in gluconeogenesis
3. Transition from glycolysis to the TCA cycle
4. End of anaerobic glycolysis (major pathway in RBCs, leukocytes, kidney medulla, lens, testes, and cornea)

TCA cycle (Krebs cycle)

Products, location, substrates

Pyruvate → acetyl-CoA produces 1 NADH, 1 CO₂

The TCA cycle produces:
3 NADH, 1 FADH₂, 2 CO₂, 1 GTP per acetyl-CoA = 12 ATP/acetyl-CoA (2x everything per glucose)

TCA cycle reactions occur in the mitochondria.

α-ketoglutarate dehydrogenase complex requires the same cofactors as the pyruvate dehydrogenase complex (B₁, B₂, B₃, B₅, lipoic acid).

TCA cycle components (8)

"Citrate Is Krebs' Starting Substrate For Making Oxaloacetate"

Citrate
Isocitrate
α-Ketoglutarate
Succinyl-CoA
Succinate
Fumarate
Malate
Oxaloacetate

Electron transport chain and oxidative phosphorylation

NADH electrons from glycolysis and the TCA cycle enter mitochondria via the malate-aspartate or glycerol-3-phosphate shuttle.

FADH₂ electrons are transferred to complex II (at a lower energy level than NADH).

The passage of electrons results in the formation of a proton gradient that, coupled to oxidative phosphorylation, drives the production of ATP.

ATP produced via ATP synthase:

1 NADH → 3 ATP

1 FADH₂ → 2 ATP

Oxidative phosphorylation poisons

Electron transport inhibitors

Name 4, mechanism

Rotenone
CN⁻
Antimycin A
CO

Directly inhibit electron transport, causing a ↓ proton gradient and block of ATP synthesis

Oxidative phosphorylation poisons

ATPase inhibitors

Name 1, mechanism

Oligomycin

Directly inhibit mitochondrial ATPase, causing an ↑ proton gradient.

No ATP is produced because electron transport stops

Oxidative phosphorylation poisons

Uncoupling agents

Name 3, mechanism

2,4-DNP
Aspirin (fevers often occur after aspirin overdose)
Thermogenin in brown fat

↑ permeability of membrane, causing a ↓ proton gradient and ↑ O₂ consumption.

ATP synthesis stops, but electron transport continues.

Produces heat

Gluconeogensis, irreversible enzymes (4)

1. Pyruvate carboxylase (mitochondria)

2. PEP carboxylase (cytosol)

3. Fructose-1,6-bisphosphatase (cytosol)

4. Glucose-6-phosphatase (ER)

"Pathway Produces Fresh Glucose"

Gluconeogensis, irreversible enzymes

Pyruvate carboxylase

Location, reaction, requirements

Mitochondria

[Pyruvate → oxaloacetate]

Requires biotin, ATP. Activated by acetyl-CoA

Gluconeogensis, irreversible enzymes

PEP carboxylase

Location, reaction, requirements

Cytosol

[Oxaloacetate → phosphoenolpyruvate]

Requires GTP

Gluconeogensis, irreversible enzymes

Fructose-1,6-bisphosphatase

Location, reaction

Cytosol

[Fructose-1,6-bisphosphate → fructose-6-P]

Gluconeogensis, irreversible enzymes

Glucose-6-phosphatase

Location, reaction

ER

[Glucose-6-P → glucose]

Gluconeogensis, irreversible enzymes

Which organ do these reactions occur? What happens if the enzymes are deficient?
What are the contributions to gluconeogenesis by odd/even-chain fatty acids?

Occurs primarily in liver. Enzymes also found in kidney, intestinal epithelium.

Deficiency of the key gluconeogenic enzymes causes hypoglycemia. (Muscle cannot participate in gluconeogenesis because it lacks glucose-6-phosphatase.)

Odd-chain fatty acids yield 1 propionyl-CoA during metabolism, which can enter the TCA cycle (as succinyl-CoA), undergo gluconeogenesis, and serve as a glucose source.

Even-chain fatty acids cannot produce new glucose, since they yield only acetyl-CoA equivalents

Hexose monophosphate (HMP) shunt (pentose phosphate pathway)

Purpose, products, sites (4)

Purpose is to provide a source of NADPH from an abundantly available glucose-6-phosphate (NADPH is required for reductive reactions, e.g. glutathione reduction inside RBCs).

Additionally, this pathway yields ribose for nucleotide synthesis and glycolytic intermediates.

2 distinct phases (oxidative and nonoxidative), both of which occur in the cytoplasm.

No ATP is used or produced.

Sites:
1. Lactating mammary glands
2. Liver
3. Adrenal cortex (sites of fatty acid or steroid synthesis)
4. RBCs

Hexose monophosphate (HMP) shunt (pentose phosphate pathway)

Oxidative and Nonoxidative pathways

Oxidative (irreversible)

Glucose-6-P → Glucose-6-P dehydrogenase (rate-limiting step) → → Products: Co₂, 2 NADPH, Ribulose-5-P

Nonoxidative (reversible)

Ribulose-5-P → Transketolases (requires B₁) → → Products: Ribose-5-P, G3P, F6P

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