What metabolic processes occur solely in the mitochondria?
Fatty acid oxidation (beta-oxidation)
acetyl-CoA production
TCA cycle
Oxidative phosphorylation
Ketogenesis
What metabolic processes occur solely in the cytoplasm?
Glycolysis
FA synthesis
HMP shunt
Protein synthesis (RER)
Steroid synthesis (SER)
What metabolic processes require reactions in both the cytosol and mitochondria?
HUGs take two"
Heme synthesis
Urea cycle
Gluconeogenesis
What is the mechanism of arsenic poisoning?
Arsenic binds lipoic acid, thereby inhibiting reactions that require lipoic acid.
This leads to decreased ATP.
(PDH, alpha-ketoglutarate dehydrogenase)
What activates Pyruvate Dehydrogenase?
Exercise:
Increased: NAD/NADH, ADP, Calcium
What are the only purely ketogenic amino acids?
Leucine and Lysine
Activate carriers:
Electrons
Acyl
CO2
1-carbon units
CH3 groups
Aldehydes
glucose
Electrons - NADH, NADPH, FADH2
Acyl - CoA, lipoamide
CO2 - biotin
1-carbon units - THF
CH3 groups - SAM
Aldehydes - TPP
glucose - UDP glucose
Main processes using:
NAD+
NADP+
NAD+ - catabolic
NADP+ - anabolic (steroid and FA synthesis)
NADPH is used in?
1. Anabolic processes (steroid and FA synthesis)
2. Respiratory burst (phagolysosomes)
3. P-450
4. Glutathione reductase
What enzyme phosphorylates glucose in the first step of glycolysis in the liver and beta pancreas cells?
In all other cells?
Liver and beta-cells of pancreas = glucokinase
All other cells - hexokinase
Differences between glucokinase and hexokinase
Hexokinase
High afinity (low Km), low capacity (low Vmax)
Uninduced by insulin
Feedback inhibited by G6P
Glucokinase
Low affinity (hi Km), high capacity (hi Vmax); loc in liver and pancreas
Induced by insulin
No direct feedback inhibition
What inhibits PFK-1?
What stimulates PFK-1?
PFK-1 inhibitors:
ATP, Citrate
PFK-1 stimulators:
AMP, F-2,6-BP
What is the relationship between FBPase-2 and PFK-2?
In what organ do they reside?
They're part of the same E complex but respond in opposite manners to phosphorylation by protein kinase A.
The liver!
Fasting state effect on FBPase-2/PFK-2 complex?
Fasting --> inc glucagon --> inc cAMP --> inc protein kinase A -->
inc activity of FBPase-2 --> F6P, inhibiting glycolysis, stimulating gluconeogenesis to provide glucose to bloodstream
Fed state effect on FBPase-2/PFK-2 complex?
Fed --> inc insulin --> dec cAMP --> dec protein kinase A -->
Increased activity of PFK-2 --> increased F-2,6-BP --> increased activity of PFK-1 --> stimulation of glycolysis
Pyruvate kinase regulation:
Stimulates:
Inhibits:
Stimulates: F-1,6-BP
Inhibits: ATP, Alanine
PDH regulation:
Stimulates:
Inhibits:
Stimulates:
Inhibits: ATP, NADH, AcetylCoA
What are the 4 things pyruvate can become?
1. Lactate (Cori cycle - liver; lactate shuttle btwn type 1 and 2 myocytes)
2. Acetyl-CoA (TCA)
3. Alanine (carries amino grps to liver from mucsle)
4. OAA (gluconeogenesis)
What is the purpose of the Cori cycle?
Shifts metabolic burden to the liver.
Use lactate generated during anaerobic metabolism to undergo hepatic gluconeogenesis and become a source of glucose for muscle/rbc's.
What is the net loss in ATP in the Cori cycle?
4 ATP / cycle
How do NADH electrons from glycolysis and TCA enter the mitochondria?
Malate-aspartate or glycerol-3-phosphate shuttle
To what are electrons from FADH2 transferred?
Complex II
Why can't muscle perform gluconeogenesis?
Muscle lacks glucose-6-phosphatase
What FAs can ultimately be used to produce glucose?
Odd-chain FAs
--> 1 propionyl-CoA --> methylmalonyl-CoA --> Succinyl-CoA
Requires biotin, Vit B12
ECFA's can make AcetylCoA, and thus can NOT be used to make glucose.
What is the purpose of the HMP shunt?
Where does it occur in cell? In body?
How much ATP is used, produced?
Provide source of NADPH (glutathione reduction) and ribose (nucleic acid synthesis)
Cytoplasm
Lactating mammary glands, rbc's, liver, adrenal cortex
No ATP is used or produced.
What is the key enzyme in the HMP shunt?
Glucose-6-dehydrogenase
From 1 G6P rxn yields 2 NADPH, one ribulose-5-P (precursor to PRPP (nucleotide synthesis)
The activity of which enzyme in the HMP shunt is measured to diagnose Wernicke-Korsakoff syndrome?
(Erythrocyte) Tranketolase activity.
Transketolase requires thiamine as a cofactor
What is the purpose of the Respiratory/Oxidative Burst?
Make free radicals/reactive oxygen intermediates to kill bugs.
What enzyme to neutrophils and monocytes, but not macrophages, possess in the respiratory burst that produces bleach?
Myeloperoxidase
How do our cells protect themselves from H2O2?
1. Catalase (H2O2 + 2 GSH --> 2 H2O + GSSG
2. Glutathione Reductase
(GSSG + NADPH --> NADP+ + 2 GSH)
What enzyme is lacking in Chronic Granulomatous disease?
Can they still make a respiratory burst?
What bugs are these patients most at risk for infection from?
NADPH oxidase.
Yes, by using the hydrogen peroxide generated by invading organisms.
Catalase-positive = S. aureus.
It has catalase, so it breaks down it's H2O2 before human can use it.
In contrast, CGD pt's can kill Streptococcus because it does not conta
What is an alternative method of trapping sugar monomers inside the cell (versus phosphorylation)?
Convert it to an alcohol, which cannot cross membrane.
This is achieved by Aldose Reductase.
Glucose --> sorbitol
Galactose --> galactitol
What is the alcohol counterpart of glucose?
sorbitol
How does prolonged hyperglycemia damage tissue?
What enzymes are involved?
What tissues are preferentially damaged and why?
1. Non-enzymatic glycosylization (of basement membrane --> increased permeability)
2. Oncotic damage. Aldose reductase converts glucose to sorbitol, which is osmotically active.
Tissues that lack the E that converts sorbitol to fructose (sorbitol dehydrog
What may follow a rotavirus infection?
Lactase deficiency
What are the essential amino acids?
PVT. TIM HALL
Phenylalanine, Valine, Threonine
Tryptophane, Isoleucine, Methionine
Histidine, Arginine, Lysine, Leucine
What are glucogenic amino acids?
Met
Val
Arg
His
Ketogenic amino acids?
Leu
Lys
Become essential in Pyruvate dehydrogenase deficiency
Form ketone bodies
What is the mechanism of hemolytic anemia in glycolytic enzyme deficiency?
What is the most common glycolytic E deficiency?
MECH - inability to maintain Na/K/ATPase --> inc osmotic pressure --> rbc swelling and lysis
Pyruvate kinase
Glucogenic AND ketogenic amino acids?
Ile
Phe
Thr
Trp
What amino acids are required during growth?
Arg
His
Ordinarily, Careless Crappers Are Also Frivolous About Urination
Molecules in Urea Cycle
Ornithine
Carbamoyl phosphate
Citrulline
Aspartate
Argininosuccinate
Fumarate
Arginine
Urea
What is the purpose of the urea cycle?
In what cellular compartment does it occur?
Convert the excess nitrogen (NH4+) created by amino acid catabolism into urea, which is excreted by the kidneys.
Mitochondria AND cytoplasm of hepatocytes
What is the structure of urea?
Urea - NH2CONH2
What is the purpose of the Alanine cycle?
Transport ammonium produced in muscles through the blood in a nontoxic form (alanine).
Deliver to liver, which can ultimately convert it to urea and excrete it.
What are two possible causes of hyperammonemia?
Mechanism of damage d/t hyperammonemia?
1. Urea cycle enzyme deficiency (OTC deficiency)
2. Liver disease
MECH - Excess NH4+ --> depletes alpha-ketoglutarate --> inhibition of TCA cycle
What are the symptoms hyperammonemia?
tremor, slurred speech, somnolence, vomiting, cerebral edema, blurred vision
What are the aminotransferase enzymes called?
What cofactor do they rely on?
AST = Aspartate aminotransferase
ALT = Alanine aminotransferase
Vit B6 = pyridoxine
Amino Acid Derivatives
Histidine
Glycine
Arginine
Glutamate
Amino Acid Derivatives
Histidine --> Histamine (B6-dep)
Glycine --> Porphyrin (B6) --> Heme
Arginine --> Creatine, urea, nitric oxide
Glutamate --> GABA (B6), Glutathione
Tryptophan derivatives
Niacin (B6-dependent process)
Serotonin (BH4-dependent process) --> Melanin
What mechanisms can cause albinism?
1. Tyrosinase deficiency - can't synthesize melanin (AR)
2. Defective tyrosine transporter --> dec amt of tyrosine and thus melanin
3. Lack of migration of neural crest cells
What is the consequence of albinism?
What genetic phenonemon does albinism exhibit?
Increased incidence of skin cancer
Variable inheritance d/t locus hetergeneity
(Vs. ocular albinism - XR)
What are the mechanisms of homocysteinuria
All AR:
1. Cystathionine synthase deficiency
(Tx - dec Met, inc Cys, folate, B12)
2. Dec affinity of cystathionine synthase for pyridoxal phosphate
(Tx - inc Vit B6 in diet)
3. Homocysteine methyltransferase deficiency
I Love Vermont maple syrup
Ile, Leu, Val
Amino acids that build up in Maple Syrup Urine Dz
MECH of glucagon's effect inside cell
Glucagon --> Adenyly cyclase --> cAMP --> PKA --> phospohorylates Glycogen phosphorylase kinase, making it active --> phosphorylates glycogen phosphorylase, making it active --> glycogen BREAKDOWN
What molecules/H's affect glycogen metabolism? In which cells?
GLYCOGENOLYSIS:
Glucagon - liver
Epinephrine - liver AND muscle
GLUCONEOGENESIS:
Insulin
In myocytes, what pairs glycogenolysis with muscle activity?
Ca++/Calmodulin
By phosphorylating glycogen phosphorylase kinase (--> active form)
MECH of insulin's effect inside hepatocyte:
Insulin --> dimerization of tyrosine kinase R --> activates protein phosphatase --> dephosphorylation of glycogen phosphorylase kinase and dephosphorylation of glycogen phosphorylase --> glycogen SYNTHESIS
Glycogen bonds:
Branches
Linkages
Branches - alpha-1,6
Created by: Branching enzyme
Broken by: Debranching enzyme
Linkages - alpha-1,4
Created by: glycogen synthase
Cleaved by: glycogen phosphorylase
What are the glycogen storage diseases?
What do they all result in?
Very Poor Carbohydrate Metabolism"
V - von Gierke's
P - Pompe's
C - Cori's
M - McArdle's
Abnormal accum of glycogen w/in cells
Inheritance pattern of lysosomal storage diseases?
Autosomal recessive
Except Fabry's and Hunter's
"X marks the spot for a Fabry Hunter
Early death d/t lysosomal storage disease?
Tay-Sachs
Niemann-Pick
Krabbe's
MECH of lysosomal storage diseases
Deficiency in one of many lysosomal E's --> accum of abnormal metabolic products
What are the mucopolysaccharidoses?
Hurler's, Hunter's, Scheie's, ~ I-Cell
Which of the mucopolysacchardisoses has corneal clouding?
Hurler's, Scheie's, I-cell
NOT Hunter's
Which of the mucopolysacchardisoses has mental retardation?
Hurler's, Hunter's (+/- I-Cell)
NOT Scheie's
Increased incidence of which sphingolipidoses in Ashkenazi Jews
Tay-Sachs
Niemann-Pick
Gaucher's
Fatty acid degradation occurs where its products will be consumed, in the
mitochondria
What shuttle is used for the synthesis of FAs?
For the degradation of FAs?
SYtrate = SYnthesis
CARnitine = CARnage of FAs
Synthesis - Citrate shuttle
Acetyl-CoA from mc --> cytoplasm
Degradation - Carnitine shuttle
Acyl-CoA from cytoplasm --> mc
What cofactor is needed for the rate-determining step of FA synthesis?
biotin
adds CO2 to acetyl-CoA --> malonyl-CoA
MECH of ketone body synthesis:
In prolonged starvation and DKA?
In alcoholism?
Prolonged starvation and DKA:
OAA is depleted for gluconeogenesis
Alcoholism:
Excess NADH shunts OAA to malate
Both:
Stall TCA --> glucose and FFA --> KB's
In other words, AcCoA > capacity of TCA
What are the three ketone bodies?
Acetoacetate, beta-hydroxybutyrate, acetone
Which ketone body is present in greatest concentration?
beta-hydroxybutyrate
Ketone bodies:
Made from?
Metabolized by brain to?
Excreted in?
HMG-CoA
2 molecules of actetyl-CoA
Exrected in urine
Ingredients for hepatic gluconeogenesis:
From peripheral tissue?
From adipose tissue?
peripheral tissue: lactate, alanine
adipose tissue: glycerol, propionyl-CoA (from OCFA)
Rate limiting step in cholesterol synthesis?
HMG CoA reductase
"you should reduce your cholesterol"
Inhibited by statins
2/3 of plasma cholesterol is esterified by
LCAT - lecithin-cholesterol acyltransferase
Essential fatty acids
Linoleic acids, linolenic acids
Arachidonic acid, if linoleic acid is absent
Fxn of pancreatic lipase?
degradation of dietary TG in small intestine
Fxn of lipoprotein lipase?
degradation of TG circulating in chylo's and VLDL
Fxn of hepatic TG lipase?
degradation of TG remaining in IDL
Fxn of Hormone-sensitive lipase?
degradation of TG stored in adipocytes
Fxn of LCAT?
catalyze esterification of cholesteral --> CE
(nascent HDL --> mature HDL)
Fxn of cholesterol ester transfer protein (CETP)?
mediate transfer of cholesterol esters to other lipoprotein particles
Fxn of apolipoprotein A-I?
Activates LCAT
Fxn of apolipoprotein B-100?
Binds LDL R, mediates VLDL secretion
(present on IDL, VDL, LDL,
NOT HDL)
Fxn of apolipoprotein C-II
Cofactor for LPL
Fxn of apolipoprotein B-48?
mediates chylomicron secretion from GI
Fxn of apolipoprotein E?
mediates Extra (remnant) uptake
Fxn of apolipoprotein C-III
inhibits LPL