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Flashcards in Metabolism Deck (191):
1

Glycolysis Pathway

Glucose --> [Hexokinase/Glucokinase] --> G6P --> F6P --> [PFK] --> F-1,6-bP --> DHAP + G3P
DHAP --> G3P
G3P ->->-> PEP --> [Pyruvate Kinase] --> Pyruvate

2

Glycogen synthesis pathway
Glycogen breakdown pathway

G6P --> G1P --> [UDP Glucose Pyrophosphorylase] --> UDP-Glucose --> [Glycogen Synthase] --> Glycogen --> [Branching Enzymes] --> Branched Glycogen
Glycogen --> [Glycogen Phosphorylase] --> G1P --> G6P
Branched Glycogen --> [Debranching enzymes] --> Limit Dextrin --> [Debranching enzymes] --> Linear Glycogen

3

How does Galactose enter Glycolysis?

Galactose --> [Galactokinase] --> Galactose-1-Phosphate --> [Galactose-1-Phosphate Uridyltransferase] --> G1P --> G6P

4

HMP Shunt pathway

G6P --> [G6PD] --> 6-phosphogluconolactone ->->-> Ribulose-5-Phosphate ->->-> [Transketolase + Thiamine] ->->-> F6P

5

How does Fructose enter glycolysis

Fructose --> [Fructokinase] --> F1P --> [Aldolase B] --> DHAP + Glyceraldehyde
Both DHAP and Glyceraldehyde are converted into G3P
OR...
Fructose --> [Hexokinase] --> F6P

6

Gluconeogenesis pathway

Pyruvate --> [pyruvate carboxylase + Biotin] --> Oxaloacetate --> [PEP carboxykinase] --> PEP ->->-> F-1,6-bP --> [F-1,6-bisphosphatase] --> F6P --> G6P --> [G6Phosphatase] --> Glucose

7

Cholesterol synthesis pathway

Acetyl CoA --> Acetoacetyl-CoA --> HMG CoA --> [HMG CoA Reductase] --> Mevalonate ->->-> Cholesterol

8

β-hydroxybutyrate synthesis pathway

2Acetyl CoA --> Acetoacetyl CoA --> HMG CoA --> Acetoacetate
Acetoacetate + NADH --> [β-hydroxybutyrate Dehydrogenase] --> β-hydroxybutyrate + NAD
Reaction is reversed in brain to produce NADH

9

TCA cycle Pathway

"Citrate Is Krebs' Starting Substrate For Making Oxaloacetate"
Pyruvate --> [Pyruvate Dehydrogenase] --> Acetyl CoA
Acetyl CoA + Oxaloacetate --> [Citrate Synthase] --> Citrate --> Isocitrate --> [Isocitrate dehydrogenase] --> α-ketoglutarate --> [α-ketoglutarate dehydrogenase + Thiamine] --> Succinyl-CoA --> Succinate --> Fumarate --> Malate --> Oxaloacetate

10

How do odd chain fatty acids and VMIT enter TCA cycle

Propinoyl-CoA --> [Biotin] --> Methylmalonyl CoA --> [B12] --> Succinyl CoA

11

How much ATP does Glucose produce in Heart and Liver

Aerobic Metabolism produces 32 ATP via malate-aspartate shuttle

12

How much ATP does Glucose produce in Muscle?

Aerobic Metabolism produces 30 ATP via Glycerol-3-Phosphate shuttle

13

How much glucose does Anaerobic Glycolysis produce

2 ATP per Glucose

14

Carrier Molecule ATP carries

Phosphoryl groups

15

Carrier Molecules NADH, NADPH, and FADH2 carries

Electrons

16

Carrier Molecules Coenzyme A, Lipamine carries

Acyl Groups

17

Carrier Molecule Biotin carries

CO2

18

Carrier Molecule THF carries

1 carbon units

19

Carrier Molecule SAM carries

CH3 groups

20

Carrier Molecule TPP carries

Aldehydes

21

NADH vs NADPH

NAD is Catabolic
NADP is Anabolic

22

NADPH
What process produces it?
What kind of reaction?
What reactions is it used in?

Produces in HMP shunt
Reduction reactions
Used in anabolic processes (Steroid and Fatty Acid Synthesis), Respiratory Burst, P450, Glutathione Reductase

23

Hexokinase
Reaction
Where is it?
Affinity
Capacity
Regulation

Glucose --> G6P
Ubiquitous
High Affinity (low Km)
Low Capacity (low Vmax)
Uninduced by insulin. Feedback inhibition by G6P

24

Glucokinase
Reaction
Where is it?
Affinity
Capacity
Regulation

Glucose --> G6P
Liver and β cells of Pancreas
Low Affinity (high Km)
High Capacity (high Vmax) "GLUcokinase is a GLUtton, it cannot be satisfied"
Induced by Insulin.

25

General glucose regulation

At low [glucose], hexokinase sequesters glucose in the tissues.
At high [glucose], excess glucose is stored in the liver

26

Net Glycolysis Reaction

Glucose + 2P + 2ADP + 2NAD --> 2Pyruvate + 2ATP + 2NADH + 2H + 2H2O

27

F-2,6-BP
Reaction that produces it and degrades it
What does it activate and what are the consequences of that?
Pathways in Fed vs Fasting state?

F6P --> [PFK-2] --> F-2,6-BP --> [FBPase2] --> F6P
F-2,6-BP activates PFK1 and pushes balance towards glycolysis
PFK2 is active in fed state
Fasting state: Glucagon --> ↑cAMP --> ↑PKA --> ↑ FBPase2, ↓ PFK2, less glycolysis
Fed state: Insulin --> ↓cAMP --> ↓PKA --> ↓ FBPase2, ↑ PFK2, more glycolysis

28

Pyruvate Dehydrogenase Complex
Reaction
# of enzymes
# of cofactors with names
What activates it?
What complex is similar?
Regulation

Pyruvate + NAD + CoA --> Acetyl-CoA + CO2 + NADH
3 enzymes
5 cofactors (TPP, FAD, NAD, CoA, Lipoic Acid) "Tender Loving Care For Nancy"
Activated by ↑ NAD/NADH ratio, ↑ADP, ↑Ca
α-ketoglutarate dehydrogenase complex is similar
Inhibited by ATP, AcetylCoA, and NADH

29

Arsenic
Mechanism of toxicity
Findings

Inhibits Lipoic acid
Vomiting, rice water stool, garlic breath

30

Pyruvate Dehydrogenase Complex Deficiency
Mutation
PathoPhys
Findings
Treatment

X linked gene for E1-α subunit
Backup of substrates (pyruvate and alanine) --> lactic acidosis
Neurological defects starting in infancy
Intake of ketogenic nutrients (high fat or high in lysine and leucine)
"Lysine and Leucine - the onLy pureLy Ketogenic AA"

31

Pyruvate Metabolism Pathway

Pyruvate ↔ [ALT w/ B6] ↔ Alanine which carries amino groups to liver from muscle
Pyruvate + CO2 + ATP ↔ [Pyruvate Carboxylase w/ Biotin] ↔ Oxaloacetate which can replenish TCA cycle or be used in gluconeognesis
Pyruvate + NAD ↔ [Pyruvate Dehydrogenase] ↔ NADH + CO2 + Acetyl Coa
Pyruvate + NADH ↔ [Lactic Acid Dehydrogenase w/ B3] ↔ NAD + Lactic Acid which is the end product of anaerobic glycolysis (major pathway in RBCs, Leukocytes, Kidney Medulla, Lens, Testes, Cornea)

32

What does the TCA cycle produce?

3NADH, 1FADH2, 2CO2, and 1GTP per 1Acetyl CoA

33

Where does the TCA cycle occur?

In the Mitochondria

34

Regulation of Citrate Synthase

Inhibited by ATP

35

α-ketoglutarate dehydrogenase regulation

Inhibited by SuccinylCoA, NADH, and ATP

36

What reactions of the Krebs Cycle produce NADH

Isocitrate --> α-ketoglutarate
α-ketoglutarate --> Succinyl CoA
Malate --> Oxaloacetate

37

What reactions of the Krebs Cycle produce GTP

Succinyl CoA --> Succinate

38

What reactions of the Krebs Cycle produce FADH2

Succinate --> Fumarate

39

How does NADH get into the Mitochondria?

Malate Aspartate or Glycerol-3-Phosphate shuttle

40

Malate Aspartate Shuttle

Cytoplasm: NADH + OAA --> NAD + Malate
Malate/α-ketoglutarate antiporter transports Malate into matrix
Matrix: NAD + Malate --> OAA + NADH
OAA + Glutamte --> Aspartate + α-ketoglutarate
Asp/Glu antiporter transports Asp into cytoplasm

41

Glycerol-3-Phosphate Shuttle

Cytoplasm: NADH + DHAP --> NAD + G3P
@ Mito inner membrane:
G3P + FAD --> [G3PDH] --> DHAP + FADH2

42

ETC Complex I
Reaction
Pumping
Inhibitor?

NADH --> NAD and CoQ
H pumped out
Rotenone

43

ETC Complex II
Name
Reaction
Pumping?

Succinate Dehydrogenase
FADH2 --> FAD and CoQ
No protons pumped thus lower energy level

44

Complex III
Reaction
Pumping
Inhibitor

CoQ transfers electrons to Cytochrome c
H pumped out
Antimycin A

45

Complex IV
Reaction
Pumping
Inhibitor

2 Cytochrome c gives electrons to 1 O2 to produce H2O
H pumped out
Cyanide and CO

46

Complex V
Reaction
Pumping
Inhibitor

ADP + P --> ATP
H moves into matrix
Oligomycin

47

How many ATP does NADH produce?

2.5

48

How many ATP does FADH produce?

1.5

49

Uncoupling agents
MoA
PathoPhys
What happens to ATP synthesis and the ETC?
What is produced?
Names

↑ permeability of membrane
↓ proton gradient and ↑ O2 consumption
ATP synthesis stops but ETC continues
Heat is produced
2,4-DNP, Aspirin (fevers occur after OD), Thermogenin in brown fat

50

Irreversible Enzymes in Gluconeognesis
Enzyme, Reaction, Location

"Pathways Produce Fresh Glucose"
Pyruvate Carboxylase, Pyruvate --> OAA, Mito
PEP carboxykinase, OAA --> PEP, Cytoplasm
F-1,6-bPase, F-1,6,bP --> F6P, Cytoplasm
G6Pase, G6P --> Glucose, ER

51

Pyruvate Carboxylase
Reaction
Regulation

Pyruvate + ATP --> OAA + ADP
Requires Biotin. Activated by Acetyl-CoA

52

Required cofactor of PEP Carboxykinase

GTP

53

What tissues are capable of gluconeogenesis

Occurs primarily in Liver
Also in Kidney and Intestinal Epithelium

54

What is the result of a deficiency in the enzymes of Gluconeognesis?

Hypoglycemia

55

What tissues care not capable of gluconeogenesis? Why?

Muscles because they lack G6Pase

56

Can fatty acids participate in gluconeogenesis?

Odd chain fatty acids yield propinoyl-CoA which enters TCA cycle as succinyl CoA and can undergo gluconeogenesis
Even chain fatty acids cannot produce new glucose since they yield only acetyl CoA equivalents

57

HMP Shunt
What does it produce?
What are the phases?
Where does it occur?
ATP?
Sites where it happens?

Provides a source of NADPH from G6P and Ribose for nucleotide synthesis and glycolytic intermediates
2 distinct phases (oxidative and nonoxidative)
Occurs in Cytoplasm
No ATP is used or produced
Sites of FA or steroid synthesis: Lactating mammary glands, Liver, Adrenal Cortex
Also RBCs

58

NADPH in RBCs

Glutathione reduction

59

Oxidative reaction of HMP shunt
Pathway
Regulation
Reversible?

G6P + NADP --> [G6PDH] --> NADPH + CO2 + Ribulose-5-Phosphate
Inhibited by NADPH
Irreversible rate limiting step

60

Nonoxidative reaction of HMP shunt
Pathway
Regulation
Reversible?

Ribulose-5-Phosphate --> [Phosphopentose isomerase, Transketolases] ->->-> Ribose-5-Phosphate + G3P + F5P
Requires B1
Reversible

61

Respiratory Burst
AKA
Cells that do it?
Role in what system?
Function

Oxidative Burst
Neutrophils and Monocytes
Plays an important role in the immune system response
Rapid release of Reactive Oxygen Intermediates

62

Oxidative Burst Pathway

O2 + NADPH --> [NADPH Oxidase] --> O2-* + NADP
O2-* --> [Superoxide dismutase] --> H2O2
H2O2 + Cl --> [Myeloperoxidase] --> HOCl*
HOCl* kills bacteria

63

Chronic Granulomatous Diseases
Deficiency
Can they fight infection? How?
What are they at risk for?

NADPH oxidase deficiency
Can use H2O2 generated by invading organisms to fight disease
At risk for infection by catalase + species (S aureus and Aspergillus)

64

How is H2O2 neutralized by bacteria?

H2O2 --> [bacterial catalases] --> H2O and O2

65

How is H2O2 neutralized in human cells?

H2O2 + Glutathione-SH (reduced) --> [Glutathione Peroxidase] --> H2O + GSSG (oxidized)
GSSG + NADPH --> [Glutathione Reductase] --> GSH + NADP
NADP + G6P --> [G6PDH] --> NADPH + 6-Phosphogluconate

66

Why is it necessary to keep Glutathione reduced? What keeps it reduced?

Reduced Glutathione can detoxify free radicals
NADPH keeps it reduced

67

G6PDH
Reaction
What happens if there is a deficiency?

G6P + NADP --> 6PG + NADPH
Deficiency results in ↓ NADPH

68

PathoPhys of G6PDH Deficiency

Low NADPH in RBCs leads to hemolytic anemia, due to poor RBC defense against oxidizing agents (Fava Beans, Sulfonamides, Primaquine, AntiTB drugs)
Infections can also precipitate hemolysis (free radicals generated via inflammatory response can diffuse into RBCs and cause oxidative damage)

69

G6PDH Deficiency
Inheritance
Epidemiology
What does it confer?
Histo

X linked recessive
Most common human enzyme deficiency. More prevalent among blacks
Confers Malarial Resistance
Heinz Bodies: Oxidized Hemoglobin precipitated within RBCs
Bite Cells: Phagocytic removal of Heinz bodies by splenic macs
"Bite into some Heinz Ketchup"

70

Essential Fructosuria
Mutation
Inheritance
Danger?
Symptoms?
Findings

Defect in Fructokinase
Autosomal Recessive
Benign
Asymptomatic since fructose is not trapped in cells
Fructose appears in blood and urine

71

Fructose intolerance
Mutation
Inheritance
What accumulates and what are the consequences?
Symptoms
Treatment

Defect in Aldolase B
Autosomal Recessive
F1P accumulates --> ↓ in available P --> Inhibition of glycogenolysis and gluconeogenesis
Hypoglycemia, Jaundice, Cirrhosis, Vomiting
↓ intake of fructose and sucrose (glucose + fructose)

72

Galactokinase Deficiency
Mutation
What accumulates
Inheritance
How bad?
Symptoms

Mutation in Galactokinase
Galactitol accumulates
Autosomal Recessive
Mild Condition
Galactose in blood and urine, Infantile Cataracts. May initially present as failure to track objects or to develop a social smile

73

Classic Galactosemia
Mutation?
Inheritance
What leads to damage?
Symptoms
Treatment

Galactose-1-Phosphate Uridyltransferase
Autosomal Recessive
Damage caused by accumulation of toxic substances (including galactitol) which accumulates in the lens of the eye
"I Just Fed Her Milk"
Failure to thrive, Jaundice, Hepatomegaly, Infantile Cataracts, Mental Retardation
Exclude galactose and lactose (galactose + glucose) from diet

74

How is Galacititol made?

Galactose --> [Aldose Reductase] --> Galactitol
Made when [galactose] is high

75

Sorbitol
Why is it made?
What is it?
Pathway
What else can be made into it?

Made as an alternative method for trapping glucose in the cell
Alcohol counterpart to glucose
Glucose + NADPH --> [Aldose Reductase] --> Sorbitol + NAD
High galactose can also result into conversion into Sorbitol

76

What is the fate of Sorbitol
Pathway
What tissues have an insufficient amount of this enzyme?

Sorbitol + NAD --> [Sorbitol Dehydrogenase] --> Fructose + NADH
Schwann cells, Retina, and Kidneys only have Aldose Reductase and are thus at risk for osmotic damage (Cataracts, Retinopathy, Peripheral Neuropathy)

77

Which tissues have both Aldose Reductase and Sorbitol Dehydrogenase?

Liver, Ovaries, Seminal Vesicles

78

Lactase Deficiency
What causes it?
Epidemiology
Self Limiting Kind?
Symptoms
Treatment

Age Dependent or Hereditary Lactose Intolerance due to loss of brush border enzyme
African Americans and Asians
May follow gastroenteritis
Bloating, cramps, osmotic diarrhea
Avoid dairy products or add lactase pills to diet

79

What kind of AA are found in proteins?

Only L form

80

Essential AA
What are they?
Glucogenic
Glucogenic/Ketogenic
Ketogenic

Need to be supplied in the diet
Met, Val, His
Ile, Phe, Thr, Trp "WIFT"
Leu, Lys

81

Acidic AA

Asp and Glu

82

Basic AA

Arg, Lys, and His
Arg is the most basic
His has no charge at body pH

83

Which AA are required during periods of growth?

Arg and His

84

Purpose of Urea Cycle

Excrete NH4+ from AA catabolism

85

Urea Cycle Pathway

"Ordinary, Careless, Crappers Are Also Frivolous About Urination"
Mito:
NH4 + CO2 + 2ATP --> [Carbamoyl Phosphate Synthase I] --> Carbamoyl phosphate
Carbamoyl Phosphate + Ornithine --> [Ornithine transcarbamoylase] --> Citrulline
Cyto:
Citrulline + Aspartate + ATP --> [Argininosuccinate Synthetase] --> Argininosuccinate (+ AMP) --> [Argininosuccinase] --> Arginine and Fumarate
Arginine + H2O --> Urea + Ornithine

86

What molecules make up Urea

NH4+, CO2, Asp

87

Alanine Cycle

Muscle: Glucose --> Pyruvate --> Alanine
Liver: Alanine --> Pyruvate --> Glucose

88

Cori Cycle

Muscle: Glucose --> Pyruvate --> Lactate
Liver: Lactate --> Pyruvate --> Glucose

89

How does NH3 go from muscles to liver?
What vitamin is important for this process?

Muscle:
AA (NH3) + α-ketoglutarate --> Glutamate (NH3) + α-ketoacids
Glutamate (NH3) + Pyruvate --> α-ketoglutarate + Ala (NH3)
Liver:
Ala (NH3) + α-ketoglutarate --> Pyruvate + Glutamate (NH3)
Glutamate --> Urea
BitB6 vital to Alpha Ketoglutarate

90

Hyperammonemia
Etiology
PathoPhys

Acquired (liver disease) or Hereditary (urea cycle enzyme deficiency)
Excess NH4+ depletes α-ketoglutarate leading to inhibition of TCA cycle

91

Hyperammonemia
Presentation
Treatment

Tremor (Asterixis), Slurring Speech, Somnolence, Vomiting, Cerebral Edema, Blurring Vision
Limit protein diet
Give benzoate or phenylbutyrate which bind AA and lead to excretion
Lactulose to acidify the GI tract and trap NH4 for excretion

92

Ornithine Transcarbamoylase Deficiency
Frequency
Inheritance
Time of onset
PathoPhys
Findings

Most common urea cycle disorder
X linked recessive (vs other urea cycle enzyme deficiencies which are AR)
Evident in first few days of life but may present with late onset
Body cannot eliminate ammonia. Carbamoyl phosphate builds up and converted into orotic acid (party of pyrimidine synthesis pathway)
Orotic acid in blood and urine, ↓ BUN, Hyperammonemia

93

Products made from Phenylalanine

Phe --> [BH4] --> Tyrosine --> [BH4] --> DOPA --> [B6] --> DA --> [VitC] --> NE --> [SAM] --> Epi
Tyrosine --> Thyroxine
DOPA --> Melanin

94

Products made from Tryptophan

Trp --> [B6] --> Niacin --> NAD
Trp --> [BH4] --> 5HT --> Melatonin

95

Products made from Histidine

His --> [B6] --> Histamine

96

Products made from Glycine

Gly --> [B6] --> Porphyrin --> Heme

97

Products made from Arginine

Arg --> Creatine
Arg --> Urea
Arg --> Nitric Oxide

98

Products made from Glutamate

Glu --> [B6] --> GABA
Glu --> Glutathione

99

Catecholamine Synthesis Pathway

Phe + THB --> [Phe Hydoxylase] --> Tyr + DHB
Tyr + DHB --> [Tyr Hydroxylase] --> DOPA + DHB
DOPA --> [DOPA Decarboxylase w/ VitB6] --> DA --> [DA-β-Hydroxylase w/ VitC] --> NE --> [Phenylethanolamine N-methyltransferase] --> Epi

100

Phenylethanolamine N-methyltransferase
Reaction
Regulation

NE --> Epi
Activated by Cortisol

101

Tetrahydrobiopterin
Names
What replenishes it?

THB or BH4
DHB + NADPH --> [Dihydropteridine Reductase] --> THB + NADP

102

Breakdown of Catecholamines
Enzymes
Products

MAO and COMT
DA --> HVA
NE --> NorMetanephrine --> VMA
Epi --> Metanephrine --> VMA

103

Phenylketonuria
Mutation
Consequences Re AAs
What builds up?
Inheritance

Mutation in Phe Hydroxylase
Tyr becomes essential
Phe builds up leading to excess phenylketones in urine
Autosomal Recessive

104

Malignant Phenylketonuria
What causes it?
Findings

Decreased THB
PKU symptoms, but after treatment pt will have elevated prolactin levels (because of low DA)

105

Phenylketonuria
Findings
Treatment
Screening

Mental Retardation, Growth Retardation, Seizures, Fair Skin, Eczema, Musty Body Odor
Treat with ↓ Phe (contained in aspartame) and ↑ Tyr in diet
Screened 2-3 days after birth (normal at birth because of maternal enzyme)

106

Phenylketones

Phenylacetate, Phenyllactate, Phenylpyruvate

107

Maternal PKU
Cause
Findings

Lack of proper dietary therapy during pregnancy
Microcephaly, Mental retardation, Growth retardation, Congenital heart defects

108

Alkaptonuria
AKA
Mutation
Inheritance
Danger?
Findings

Ochronosis
Deficiency of Homogentisic Acid Oxidase in the degradative pathway of Tyr to Fumarate
AR and Benign
Dark connective tissue, Brown pigmented sclera, Urine turns black on prolonged exposure to air, Debilitating arthralgias (homogentisic acid is toxic to cartilage

109

Albinism
Defect
Inheritance
Risk

Defective Tyrosinase which converts Tyr --> Melanin. AR
Defective Tyr transporter (low amounts of Tyr and thus melanin)
Lack of migration of Neural Crest Cells
Variable inheritance
Risk of Skin Cancer

110

Inheritance of ocular albinism

X linked recessive

111

Homocystinuria
Inheritance
Cause w/ Treatment

AR
1. Cystathionine Synthase Deficiency. ↓ Met and ↑ Cys, B12, and Folate in diet
2. ↓ affinity of cystathionine synthase for B6 (Pyridoxal Phosphate). ↑ B6 in diet
3. Homocysteine Methyltransferase Deficiency

112

Homocysteine Pathways

Homocysteine --> [Homocysteine Methyltransferase w/ B12] --> Methionine
Homocysteine + Serine --> [Cystathionine Synthase w/ B6] --> Cystathionine --> Cysteine

113

Homocystinuria
What builds up?
What happens Re AAs?
Findings
Test

Homocysteine builds up
Cysteine becomes essential
Homocysteine in urine, Mental Retardation, Osteoporosis, Tall stature, Kyphosis, Lens Subluxation (downward and inward), and atherosclerosis (Stroke and MI)
Nitroprusside Cyanide Test

114

Cystinuria
PathoPhys
Findings
Inheritance
Treatment

Defect of renal tubular AA transporter for cysteine, ornithine, lysine, and arginine in PCT of kidney
Cystine in urine --> Precipitation of hexagonal crystals and renal staghorn calculi
AR
Hydration and Urinary Alkalinization

115

What is Cystine

2 cysteines connected by a disulfide bond

116

Maple Syrup Urine Disease
PathoPhys
Findings
What does it lead to?
Inheritance

"I Love Vermont Maple Syrup from trees with Branches"
↓ in α-ketoacid dehydrogenase (B1) --> Blocked degradation of branched AA (Ile, Leu, Val)
↑ α-ketoacid in blood (especially Leu), Urine smells like maple syrup (burned sugar)
CNS defects, Mental Retardation, Death
AR

117

Hartnup Disease
Inheritance
PathoPhys
Presentation

AR
Defective Neutral AA transporter on renal and intestinal epithelial cells
Trp excretion in urine and ↓ absorption in gut --> pellagra

118

Glucagon/Epi Pathway

Glucagon/Epi --> AC --> cAMP --> PKA --> Glycogen Phosphorylase Kinase --> Glycogen Phosphorylase --> Glycogenolysis

119

Insulin Pathway

Insulin --> RTK --> Protein Phosphatase --/ Glycogen Phosphorylase Kinase and Glycogen Phosphorylase

120

Glycogen
Branch points
Linkages

α(1,6) Branches
α(1,4) Linkages

121

Fate of Glycogen in Skeletal Muscle
What regulate Glycogenonlysis during exercise?

Undergoes Glycogenolysis --> G1P --> G6P which is rapidly metabolized during exercise
Ca --> glycogenolysis

122

Glycogen in Hepatocytes

Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels

123

Debranching Enzyme Type III

Acts on Limit Dextrin (4 glucose residues in branched configuration) to produce Glucose

124

How is Glycogen degraded in lysosomes?

α-1,4-glucosidase

125

Glycogen Storage Disorders
Names
What do they result in?

"Very Poor Carb Metabolism"
Von Gierke's, Pompe's, Cori's, McArdle's
Accumulation of glycogen within cells

126

von Gierke's Disease
Type
Deficient enzyme
Findings
Inheritance

Type I
G6Pase
Fasting hypoglycemia, ↑ glycogen in liver, ↑ lactate in blood, hepatomegaly
AR

127

Pompe's Disease
Type
Deficient enzyme
Findings
Inheritance

"Pompe trashes the Pump"
Type II
Lysosomal α-1,4-glucosidase (acid maltase)
Cardiomegaly and systemic findings leading to early death (Liver, Muscle)
AR

128

Cori's Disease
Type
Deficient enzyme
Findings
Inheritance

Type III
Debranching Enzyme (α-1,6-glucosidase
Milder form of type I with normal blood lactate levels. Gluconeogenesis intact
AR

129

McArdle's Disease
Type
Deficient enzyme
Findings
Inheritance

McArdle's = Muscles
Type V
Skeletal muscle glycogen phosphorylase
↑ glycogen in muscle that cannot be broken down leading to painful muscle cramps, myoglobinuria with strenuous exercise
AR

130

Fabry's Disease
Kind of disease
Deficiency
What accumulates
Findings
Inheritance

Sphingolipidoses Lysosomal Storage Disease
α-galactosidase A
Ceramide Trihexoside accumulates
Peripheral neuropathy of hands/feet, angiokeratomas, CV/Renal disease
XR

131

Gaucher's Disease
Kind of disease
Deficiency
What accumulates
Frequency
Findings
Histo
Inheritance

Sphingolipidoses Lysosomal Storage Disease
Glucocerebrosidase
Glucocerebroside
Most common
Hepatosplenomegaly, Aseptic necrosis of femur, Bone crises, Pancytopenia, Thrombocytopenia
Gaucher's cells (macs that look like crumpled tissue paper)
AR. More common in Ashkenazi Jews

132

Niemann-Pick Disease
Kind of disease
Deficiency
What accumulates
Findings
Histo
Inheritance

"No man picks his nose with his SPHINGer"
Sphingolipidoses Lysosomal Storage Disease
Sphingomyelinase
Sphingomyelin
Progressive neurodegeneration, Hepatosplenomegaly, Cherry-red spots on macula
Foam cells
AR. More common in Ashkenazi Jews

133

Tay-Sachs Disease
Kind of disease
Deficiency
What accumulates
Findings
Histo
Inheritance

"Tay-SaX lacks heXosaminidase"
Sphingolipidoses Lysosomal Storage Disease
Hexosaminidase A
GM2 Ganglioside
Progressive neurodegeneration, Developmental delay, Cherry-red spots on macula, No hepatosplenomegaly
Lysosomes with onion skin
AR. More common in Ashkenazi Jews

134

Krabbe's Disease
Kind of disease
Deficiency
What accumulates
Findings
Histo
Inheritance

Sphingolipidoses Lysosomal Storage Disease
Galactocerebrosidase
Galactocerebroside
Peripheral neuropathy, Developmental delay, Optic atrophy
Globoid cells
AR

135

Metachromatic Leukodystrophy
Kind of disease
Deficiency
What accumulates
Findings
Inheritance

Sphingolipidoses Lysosomal Storage Disease
Arylsulfatase A
Cerebroside Sulfate
Central and peripheral demyelination with ataxia, dementia
AR

136

Hurler's Syndrome
Kind of disease
Deficiency
What accumulates
Findings
Inheritance

Mucopolysaccharidoses Lysosomal Storage Disease
α-L-iduronidase
Heparan sulfate, Dermatan sulfate
Developmental delay, Gargoylism, Airway obstruction, Corneal clouding, HSM
AR

137

Hunter's Syndrome
Kind of disease
Deficiency
What accumulates
Findings
Inheritance

"Hunter see clearly (no corneal clouding) and aim for the X"
Mucopolysaccharidoses Lysosomal Storage Disease
Iduronate Sulfatase
Heparan sulfate, Dermatan sulfate
Mild Hurler's + Aggressive behavior, No Corneal Clouding
XR

138

Lysosomal Pathways

GM2 --> [Hexosaminidase A] --> GM3 --> Glucocerebroside --> [Glucocerebrosidase] --> Ceramide
Sphingomyelin --> [Sphingomyelinase] --> Ceramide
Sulfatides --> [Arylsulfatase A] --> Galactocerbroside --> [Galactocerebrosidase] --> Ceramide

139

Where does Fatty Acid degradation occur?

In Mitochondria

140

Acyl-CoA Dehydrogenase Deficiency produces...

↑ Dicarboxylic acids, ↓ glucose and ketones

141

Carnitine Deficiency
PathoPhys
Presentation

Inability to transport LCFA into Mito resulting in toxic accumulation
Weakness, Hypotonia, Hypoketoic hypoglycemia

142

Fatty Acid Synthesis Pathway

Citrate transported out of Mito via Citrate shuttle
Citrate --> [ATP citrate lyase] --> AcetylCoA
AcetylCoA + CO2 (biotin) --> MalonylCoA --> Palmitate (16 carbons)

143

Fatty Acid Degradation Pathway

Cytoplasm:
Fatty Acid + CoA --> [FA CoA synthetase] --> Acyl-CoA
Carnitine Shuttle into Mito
Acyl-CoA --> β-oxidation (breakdown to AcetylCoA groups) --> Ketone Bodies or TCA Cycle

144

Regulation of Carnitine Shuttle

Malonyl CoA --/ Carnitine Shuttle

145

Ketone Bodies
Where are they produced
What are they produced from?
Names?
Where are they used?

Produced in liver from Fatty Acids
Acetoacetate and β-hydroxybutyrate
Used in muscles and brain

146

Circumstances that lead to ketone body formation?
PathoPhys?
What are they metabolized into?
What is it excreted into?

Prolonged starvation and diabetic ketoacidosis: OAA is depleted for gluconeogenesis
Alcoholism: Excess NADH shunts OAA to Malate
Low OAA --> stalled TCA cycle, which shunts glucose and FFA towards production of ketone bodies
Metabolized into 2 molecules of AcetylCoA
Excreted in urine

147

Urine test for ketone bodies?

Does not detect β-hydroxybutyrate which is favored by high redox state

148

Energy sources during exercise
Seconds?
Minutes?
Hours?

Stored ATP drops. Creatinine Phosphate rises and falls
Rise in Anaerobic glycolysis and Aerobic metabolism and FA oxidation with Anaerobic glycolysis larger percentage
Rise in Anaerobic glycolysis and Aerobic metabolism and FA oxidation with latter having larger percentage

149

Metabolism during fed state
What processes?
Hormones?

Glycolysis and Aerobic Respiration
Insulin stimulates storage of lipids, protein. and glycogen

150

Metabolism during fasting between meals
Processes
Hormones

Hepatic Glycogenolysis (major), Hepatic gluconeognesis, Adipose release FFA (minor)
Glucagon, Adrenaline stimulate use of fuel reserves

151

Metabolism During Starvation Days 1-3

Blood glucose levels maintained by:
1. Hepatic glycogenolysis
2. Adipose release FFA
3. Muscles and Liver shift from using glucose to using FFA
4. Hepatic gluconeogenesis from peripheral tissue lactate and Ala, and from adipose tissue glycerol and propionyl-CoA (from add chain FFA)

152

How long to glycogen reserves last?

Depleted after 1 day

153

Can RBC use ketone bodies?

No, they lack mito

154

Metabolism of Starvation after day 3

Adipose stores produce ketone bodies which become the main source of energy for the brain and heart. After these are depleted, protein degeneration accelerates leading to organ failure and death

155

What determines survival time during starvation?

Adipose stores

156

How much cholesterol is esterified?

2/3 of plasma cholesterol is esterified by lecithin-cholesterol acyltransferase (LCAT)

157

Lipid intake pathway

Chylomicrons --> [LPL] --> FFA and Chylomicron remnant
FFA taken up by adipose and peripheral tissue
Remnant taken up by liver via Apolipoprotein E

158

Hormone Sensitive Lipase

Degrades TG stores in adipocytes

159

HDL production

Liver or Intestines produce Nascent HDL
Lecithin-Cholesterol Acyltransferase (LCAT) turns nascent HDL into Mature HDL by esterification of cholesterol
Cholesterol Ester Transfer Protein (CETP) mediates transfer of cholesterol esters from HDL to VLDL, IDL, and LDL

160

Apolipoprotein E
Function
What is it in?

Mediates remnant uptake
In Chylomicron, Chylomicron Remnant, VLD, IDL, and HDL. Not LDL

161

Apolipoprotein A1
Function
What is it in?

Activates LCAT
HDL

162

Apolipoprotein C2
Function
What is it in?

Lipoprotein Lipase Cofactor
Chylomicron, VLDL, HDL

163

Apolipoprotein B48
Function
What is it in?

Mediates Chylomicron Secretion
Chylomicron, Chylomicron remnant

164

Apolipoprotein B100
Function
What is it in?

Binds LDL receptor
VLDL, IDL, LDL

165

What are lipoproteins composed of?

Cholesterol, TG, Phospholipids

166

What lipoproteins carry most cholesterol?

LDL and HDL

167

LDL
Function
How is it formed
How is it taken up?

Delivers hepatic cholesterol to peripheral tissues
Formed by hepatic lipase modification of IDL in peripheral tissue
Taken up by target cells vai receptor mediated endocytosis

168

HDL
Function
Repository for what?
What secretes it?

Mediates reverse cholesterol transport from periphery to liver
Acts as a repository for apoC and apoE (which are needed for chylomicron and VLDL metabolism)
Secreted from both liver and intestine

169

Chylomicron
Function
What secretes it?

Delivers dietary TG to peripheral tissue and Delivers cholesterol to liver in the form of remnant (which is depleted of TGs)
Secreted by intestinal epithelial cells

170

VLDL
Function
What secretes it?

Delivers hepatic TG to peripheral tissue
Secreted by liver

171

IDL
How is it formed
Function

Formed in the degradation of VLDL
Delivers TG and cholesterol to liver

172

I-Hyper-Chylomicronemia
Inheritance
PathoPhys
Blood test?
Presentation

AR
LPL deficiency or altered apoC2
↑ chylomicrons, TG, cholesterol
Pancreatitis, HSM, Eruptive/Pruritic Xanthomas, No ↑ risk for atherosclerosis

173

IIa-Familial-HyperCholesterolemia
Inheritance
PathoPhys
Blood test?
Presentation

AD
Absent of decreased LDL receptor
↑ LDL and cholesterol
Accelerated atherosclerosis, Achilles tendon xanthomas, Corneal arcus

174

IV HyperTriglyceridemia
Inheritance
PathoPhys
Blood test?
Presentation

AD
Hepatic overproduction of VLDL
↑ VLDL and TG
Pancreatitis

175

Abetalipoproteinemia
Inheritance
PathoPhys
Onset
Presentation
Histo
Presentation

AR
Defective Microsomal TG Transfer Protein (MTP) --> ↓B48 and B100 --> ↓ chylomicron and VLDL synthesis and secretion
Symptoms appear in the 1st few months of life
Biopsy shows lipid accumulation in enterocytes. Blood shows Acanthocytosis
Failure to thrive, Steatorrhea, Ataxia, Night blindness

176

What happens in Mitochondria

Fatty acid oxidation (β oxidation), Acetyl-Coa Production, TCA cycle, Oxidative Phosphorylation

177

What happens metabolically in the Cytoplasm?

Glycolysis, Fatty Acid Syntesis, HMP shunt, Protein Synthesis (RER), Steroid Synthesis (SER), Cholesterol Synthesis

178

What reactions occur in both the Mitochondria and the Cytoplasm?

"HUGs take 2"
Heme synthesis, Urea cycle, Gluconeogenesis

179

Rate limiting step of Glycolysis
Regulators

PFK1
+: AMP, F2,6BP
-: ATP, Citrate

180

Rate limiting step of Gluconeognesis
Regulators

Fructose 1,6 bisphosphatase
+: ATP
-: AMP, F2,6BP

181

Rate limiting step of TCA cycle
Regulators

Isocitrate Dehydrogenase
+: ADP
-: ATP, NADH

182

Rate limiting step of Glycogen Synthesis
Regulators

Glycogen Synthase
+: Glucose, Insulin
-: Epinephrine, Glucagon

183

Rate limiting step of Glycogenolysis
Regulators

Glycogen Phosphorylase
+: AMP, Epinephrine, Glucagon
-: Insulin, ATP

184

Rate limiting step of HMP shunt
Regulators

G6PD
+: NADP
-: NADPH

185

Rate limiting step of de novo pyrimidine synthesis

Carbamoyl Phosphate Synthetase II

186

Rate limiting step of de novo purine synthesis
Regulation

Glutamine PRPP aminotransferase
Inhibited by AMP, IMP, and GMP

187

Rate limiting step of urea cycle
Regulation

Carbamoyl Phosphate Synthetase I
Activated by N-acetylglutamate

188

Rate limiting step of Fatty Acid Synthesis
Regulation

Acetyl-CoA Carboxylase (ACC)
+: Insulin, Citrate
-: Glucagon, Palmitoyl-CoA

189

Rate limiting step of Fatty Acid Oxidation
Regulation

Carnitine Acyltransferase
Inhibited by Malonyl-CoA

190

Rate limiting step of Ketogenesis

HMG CoA Synthase

191

Rate limiting step of Cholesterol Synthesis
Regulation

HMG CoA Reductase
+: Insulin, Thyroxine
-: Glucagon, Cholesterol