Metabolism Flashcards
1
Q
Glycolysis Pathway
A
Glucose –> [Hexokinase/Glucokinase] –> G6P –> F6P –> [PFK] –> F-1,6-bP –> DHAP + G3P
DHAP –> G3P
G3P ->->-> PEP –> [Pyruvate Kinase] –> Pyruvate
2
Q
Glycogen synthesis pathway
Glycogen breakdown pathway
A
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
Q
How does Galactose enter Glycolysis?
A
Galactose –> [Galactokinase] –> Galactose-1-Phosphate –> [Galactose-1-Phosphate Uridyltransferase] –> G1P –> G6P
4
Q
HMP Shunt pathway
A
G6P –> [G6PD] –> 6-phosphogluconolactone ->->-> Ribulose-5-Phosphate ->->-> [Transketolase + Thiamine] ->->-> F6P
5
Q
How does Fructose enter glycolysis
A
Fructose –> [Fructokinase] –> F1P –> [Aldolase B] –> DHAP + Glyceraldehyde
Both DHAP and Glyceraldehyde are converted into G3P
OR…
Fructose –> [Hexokinase] –> F6P
6
Q
Gluconeogenesis pathway
A
Pyruvate –> [pyruvate carboxylase + Biotin] –> Oxaloacetate –> [PEP carboxykinase] –> PEP ->->-> F-1,6-bP –> [F-1,6-bisphosphatase] –> F6P –> G6P –> [G6Phosphatase] –> Glucose
7
Q
Cholesterol synthesis pathway
A
Acetyl CoA –> Acetoacetyl-CoA –> HMG CoA –> [HMG CoA Reductase] –> Mevalonate ->->-> Cholesterol
8
Q
β-hydroxybutyrate synthesis pathway
A
2Acetyl CoA –> Acetoacetyl CoA –> HMG CoA –> Acetoacetate
Acetoacetate + NADH –> [β-hydroxybutyrate Dehydrogenase] –> β-hydroxybutyrate + NAD
Reaction is reversed in brain to produce NADH
9
Q
TCA cycle Pathway
A
“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
Q
How do odd chain fatty acids and VMIT enter TCA cycle
A
Propinoyl-CoA –> [Biotin] –> Methylmalonyl CoA –> [B12] –> Succinyl CoA
11
Q
How much ATP does Glucose produce in Heart and Liver
A
Aerobic Metabolism produces 32 ATP via malate-aspartate shuttle
12
Q
How much ATP does Glucose produce in Muscle?
A
Aerobic Metabolism produces 30 ATP via Glycerol-3-Phosphate shuttle
13
Q
How much glucose does Anaerobic Glycolysis produce
A
2 ATP per Glucose
14
Q
Carrier Molecule ATP carries
A
Phosphoryl groups
15
Q
Carrier Molecules NADH, NADPH, and FADH2 carries
A
Electrons
16
Q
Carrier Molecules Coenzyme A, Lipamine carries
A
Acyl Groups
17
Q
Carrier Molecule Biotin carries
A
CO2
18
Q
Carrier Molecule THF carries
A
1 carbon units
19
Q
Carrier Molecule SAM carries
A
CH3 groups
20
Q
Carrier Molecule TPP carries
A
Aldehydes
21
Q
NADH vs NADPH
A
NAD is Catabolic
NADP is Anabolic
22
Q
NADPH
What process produces it?
What kind of reaction?
What reactions is it used in?
A
Produces in HMP shunt
Reduction reactions
Used in anabolic processes (Steroid and Fatty Acid Synthesis), Respiratory Burst, P450, Glutathione Reductase
23
Q
Hexokinase Reaction Where is it? Affinity Capacity Regulation
A
Glucose --> G6P Ubiquitous High Affinity (low Km) Low Capacity (low Vmax) Uninduced by insulin. Feedback inhibition by G6P
24
Q
Glucokinase Reaction Where is it? Affinity Capacity Regulation
A
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
