Week 9- Regulation of Glycolysis Fatty Acid Metabolism

Question 1

Glucose Metabolism: Overview

Answer 1

• G6P a key branch point
  1. either product of hexokinase action
  2. or product of glycogen breakdown
  3. or product of gluconeogenesis
• Fate of G6P
  1. continue glycolysis to produce ATP
  2. glycogen synthesis
  3. pentose phosphate pathway to produce NADPH and R5P

Question 2

Regulation of glycolysis

Answer 2

• regulation of glucose transporters
• regulation of hexokinase
• regulation of PFK-1
• regulation of pyruvate kinase

Question 3

Lipid metabolism: overview

Answer 3

• Lipids represent energy storage
• fatty acids catabolism in mitochondria releases acetyl-CoA
• released acetyl-CoA is oxidized in citric acid cycle and ATP produced by oxidative phosphorylation
• synthesis of fatty acids starts with acetyl-CoA
• synthesis and breakdown take place at the same time but different locations
• fatty acid synthesis is in cytoplasm

Question 4

Digestion and transport of dietary fatty acids

Answer 4

1. bile salts emulsify dietary fats in small intestine. Micelles are formed
2. Triacylglycerols are hydrolysed by lipase
3. Fatty acids from lipase action are taken up by the intestinal mucosa and resynthesized into triacylglycerols
4. Chylomicrons are produced from triacylglycerols, cholesterol, and apoproteins
5. Chylomicrons move in the bloodstream to tissues
6. Lipoprotein lipase action releases fatty acids
7. Fatty acids enter cells
8. Faty acids are oxidized as fuel or stored in triacylglycerols

Question 5

Movement of fatty acids into circulation

Answer 5

• triacylglycerol: polymeric storage form of fatty acids
• hydrolysis of triacylglycerols releases fatty acids
• fatty acids are oxidized to release 2-C acetyl-CoA
• Beside citric acid cycle, acetyl-CoA is also precursor for fatty acid synthesis

Question 6

Release of Fatty Acid from Adipocytes

Answer 6

• Hormone glucagon activates fatty acid breakaway from triacylglycerol within adipocytes
• Fatty acids released into circulation, bound to Serum Albumin, and transported to other tissues
• Fatty acids enter other cells via transporters
• Fatty acids generate acetyl-CoA via beta-oxidation

Question 7

Fatty acid activation

Answer 7

• fatty acids are activated before they are catabolised
• reaction catalyzed by acyl-CoA snythetase requires ATP
• reaction products include Acyl-CoA
• Fatty acids are activated in cytosol, but oxidized in mitochondria
• acyl group of acyl-CoA is first moved to carnitine
• acyl- carnitine shuttled into mitchondria by carnitine transporter
• acyl group moved to CoA inside mitochondria
• carnitine returns to cytoplasm by carnitine transporter

Question 8

Fatty acid Oxidation- Beta oxidation pt 1

Answer 8

• Beta oxidation is a 4 step reaction producing acetyl-CoA
  1. Formation of trans alpha-beta double bond AD, FAD is reduced and linked to the electron transport chain to produce 2 ATP
  2. Hydration of double bond by EH
  3. Dehydrogenation by HAD, NAD+ is reduced
  4. Cleavage of alpha-beta bond to produce one acetyl-CoA and shortened acyl-CoA (-2 C)

Question 9

Fatty acid Oxidation- Beta oxidation pt 2

Answer 9

• Successive removal of 2 carbon units
• Each beta oxidation generates
  1. 1 NADH
  2. 1 FADH2
  3. 1 acetyl-CoA become 1 FADH2 (via citric acid cycle) and 3 NADH
• Beta oxidation generates more acetyl groups to citric acid cycle than does glycolysis
• Beta oxidation feeds electrons directly to electron transport chain

Question 10

Fatty acid biosynthesis and beta oxidation

Answer 10

• beta oxidation in mitochondria
• biosynthesis in cytosol
• acetyl-CoA formed in mitochondria by beta oxidation
• need to transport acetyl-CoA out of mitochondria
• different cofactors are involved (NAD+ and NADPH)
• malonyl-CoA an intermediate of fatty acid synthesis
• fatty acid biosynthesis mostly active in the liver

Question 11

Fatty acid biosynthesis- comparison with beta oxidation

Answer 11

• Beta oxidation: release acetyl-CoA and generation of reduced cofactor
• Biosynthesis is the opposite

Question 12

Fatty acid biosynthesis- 1st reaction

Answer 12

• carboxylation of cytoplasmic acetyl-CoA by acetyl-CoA carboxylase
• biotin is carrier of CO2 group
• malonyl CoA is reaction product and starting point of FA biosynthesis
• FA biosynthesis involves successive addition of 2-C units to growing chain
• Addition of 2-C unit from malonyl-CoA catalyzed by fatty acid synthase

Question 13

Fatty acid biosynthesis: successive addition

Answer 13

• successive addition of 2-C unit (acetyl-CoA) using butyryl-ACP as base

Question 14

Fatty acid synthase

Answer 14

• 2 NADPH required for each round are supplied by pentose phosphate pathway
• synthesis of one palmitate (saturated C16 fatty acid) requires production of 7 malonyl-CoA, consuming 7 ATP
• 7 rounds of fatty acid synthesis consume 14 NADPH
• acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 7 H+ = palmitate + 7 CO2 + 14 NADP+ + 8CoA + 6 H2O
• 7 acetyl-CoA +7 CO2 + 7 ATP = 7 malonyl-CoA + 7 ADP + 7 Pi + 7 H+
• Overall: 8 acetyl- CoA + 14 NADPH + 7 ATP = Palmitate + 14 NADP+ + 8 CoA + 6 H2O + 7 Pi + 7 H+