Exam 2 Flashcards
•HETEs
•chemotactic agents: act on neutrophils and eosinophils
Mucopolysaccharidoses (MPS)
lysosomal storage diseases (LSDs)
inherited - defective/missing hydrolytic enz fails to degrade GAG
accumulation of GAG = coarse facial features, short stature, enlarged organs (liver, spleen)
Glucokinase Characteristics/Location
In liver: important during high [glucose]: phosphorylated glucose to liver metabolism
In pancreatic islets cells: most important glucose sensing cells in the body :
- glucose metabolismà–> ATP –> Insulin secretion
Irreversible
No G6-P feedback inhibition
Adrenoleukodystrophy (X-ALD)
• X-linked defect in ABCD1 that transports VLCFA CoAs into peroxisomes
High Fructose Corn Syrup
- Inexpensive way to sweeten food
- Modified High Fructose Corn Syrup:
- •55-45 fructose/glucose ratio:non-covalent linkage
COX 1 Site, Product, Action
GI Tract –
- PGE2
- Cytoprotection
- Anti-acid
Platelets
- Thromboxane A2
- Initiates Thrombosis
Heinz Bodies
Inclusions in RBC due to Hb damage
Absorption of Monomeric Lipids
NPC1-L1 protein in duodenum and jejunum
prox 2/3 ileum: FA, 2-monoacylglycerol, lysophospholipids
micells NOT absorbed
bile salts
- deconj by gut bac
- absorbed via ileal bile acid txper in distal ileum
- txp to liver
- reconj, recirculated
Ductus Arteriosus
•blood vessel connecting the pulmonary artery to the aorta in the fetus.
It closes 1-2 days after birth
•Indomethacin can be used to hasten the closure of the ductus arteriosus if it remains open after birth
Alprostadil® (PGE1) infusion keeps the ductus arteriosus open (patent) after birth if needed to remain
Sorbitol is a natural….
- laxative and can cause diarrhea, irritable bowel syndrome, bloating and flatulence.
- Too much sorbitol (from 10 to 50g, or more for adults) can cause gastro-intestinal problems.
Proteoglycan Aggregates
GAG attached to SER on core protein covalently via XYL-GAL-GAL
aggreg via ionic attachement to hyaluronan
bottle brush structure: charge repulsion
•Importance of OAA:
•Precursor for gng
[oaa] = rate lim for TCA
rxn can occur in reverse for malate-asp shuttle of NADH
- malate crossing into mito –> OAA + NADH
Key Enzymes of Eicosanoid Synthesis
- Phospholipase A2: The rate limiting step (inducible)
- Arachidonic acid release from membrane phospholipids
- Suppressed by steroids (glucocorticoids)
- Prostaglandin synthase (cycooxygenase/peroxidase)
- Prostaglandin and Thromboxane synthesis
- COX1 – constitutive
- COX2 – inducible
- Both irreversibly inhibited by aspirin (ASA)
- Both reversibly inhibited by non-steroidal anti-inflammatory drugs (NSAIDs)
- COX2 induction suppressed by steroids
- 5-Lipoxygenase
- Leukotriene synthesis
- Inhibited by zileuton
Pancreatic lipase
hydrolyze LCFA at positions 1 and 3
products are 2-monoacylglycerol and 2 LCFA (absorbed in ileum)
pancreatic colipase stab binding of the lipase to substate
- secr as zymogen, activ by trypsin
Allosteric Regulation of Glycogen Metabolism
•Glucose 6-P (Well fed state-(M & L)
–Inhibition of phosphorylase (Lysis)
•Glucose (liver)
–Inhibition of liver phosphorylase (Lysis)
–Glucose “sensor”
•ATP (high energy)(M & L)
–Inhibition of phosphorylase (Lysis)
•AMP(low energy)(Muscle)
–Activation of muscle phosphorylase (b) (Lysis)
•Calcium (Muscle)
–Activation of muscle phosphorylase b kinaseà + glycogenolysis
•Ca++ binds Calmodulin
Importance of CYPs enzymes in Drug metabolism
- Two most significant enzymes for drug metabolism = CYP3A4 and CYP2D6
- CYP3A4 is responsible for over 50% of drug metabolism
- Can convert prodrugàactive form
- e.g. cyclophosphamide (chemo)àactive froms crosslinks DNA
Glycogen
Phosphorylase
cleaves alpha 1,4 using P from non-reducing ends until it reaches 4 gluc units from a branch point - then debrancher acts
•Coenzyme: Pyridoxal Phosphate
(Vit B6 at active site)
•Product is Glucose 1-P
PEP Carboxykinase
(mito & cyto)
Glutathione Peroxidase (GPx)
H2O2à H2O
Need for reduced form of GSH from NADPH and GRed
Thromboxane A2 (TXA2)
- Vasoconstrictor
- Bronchoconstrictor
- Synthesized by platelets, key in platelet aggregation
Pyruvate Dehydrogenase Complex(PDHC) Reaction
- Pyruvate –> Acetyl-CoA +NADH
- Mitochondrial
- Irreversible:
- Acetyl-CoA does not form Pyruvate
•Under low blood sugar (high glucagon), how is glycolysis regulated in the liver?
inhibition of PFK-1 (main regulatory enzyme in glycolysis)
- glucagon –(-)–> F2,6BP–(-)–> PFK-1 —> glycolysis slows = less glucose is metabolized under hypoglycemia
Metabolic phenotype of Cancer cells:
ØHigh rate of glucose uptake and aerobic glycolysis –> Lactate –> exported out of cell
- ØSubmaximal activity of TCA cycle and oxidative metabolism
dec [ATP] (colon ca)
inc Nad+/NADH ratio
- ØPyruvate + H+ + NADH –> Lactate + NAD+
Ø NADP+/NADPH anabolic ratio
ØIncreased glutamine uptake and utilization
Dermatan sulfate
skin, heart valves, blood vessels
FA Phase 1 - Citrate Shuttle
- High [ATP] and [NADH] inhibit isocitrate dehydrogenase
- Citrate accumulates, goes to cytosol
- Glucose, insulin stimulate ATP:Citrate lyase
- Polyunsaturated fatty acids (PUFA), leptin inhibit ATP:Citrate lyase
No FA oxidation in
brain or in cells that lack mitochondria
What is one of the explanations for why eating sugar can lead to fat?
acetyl-CoA + OAA –(citrate synthase)–> citrate
can be shuttle out of mito and release reactants into cytosol
acetyl-COA = precursor to make fat in cytosol
citrate = allosteric activactor of 1st rxn in FA synth
Released FA are transported by
•serum albumin to liver and muscle
Main Regulatory Agents in Gluconeogenesis
REVEIW ALL
Sphingolipids
Derivatives of ceramide an ester between a fatty acid and sphingosine, an amino alcohol
The backbone of = NOT glycerol
- long-chain amino alcohol sphingosine
A fatty acid is joined to sphingosine via an amide linkage
A polar head group is connected to sphingosine by a glycosidic or phosphodiester linkage
Bypass Reaction of Hexokinase/Glucokinase
Glucose 6-Phosphatase (G 6-Ptase)
Releases free glucose –> blood
Not in Muscle
Muscle does not maintain blood glucose homeostasis
Transmembrane Endoplasmic Reticulum protein
effects of methanol –> formaldehyde
toxic to optic N and can produce blindness
high doses = fatal
Deficiency of AGPAT is associated with
•congenital generalized lipodystrophy (absence of adipose tissue and fatty liver)
Methanol metabolism
spiked drink - common in antifreeze
—>formaldehyde
toxic to optic nerve and can produce blindness.
In high doses, formaldehyde may be fatal
Bottom line: Prostanoids signal
signal through multiple second messengers and their effects are determined by specific receptor subtypes in target tissues
Prostanoids Signal Via GPCR
NSAIDs
- non-selective, reversible COX inhibitors (e.g., ibuprofen)
- Analgesic, anti-inflammatory and antipyretic
- Inhibit the production of both PG and TX
secretion of _______ in MPS III
HS, KS
ØHow does the body transport glucose out of the blood into the tissues?
- SGLT-1 and SGLT-2 for glucose absorption from intestines and kidney
- Use of SGLT-2 inhibitors to prevent renal reabsorptionà lower blood glucose
Detrimental Effects F1P pathway in completion
F1P -> g3p -> -> pyr-> acetyl-coa-> citrate->–>–> fats-> VLDL
fats + increase [VLDL] -> obesity, dyslipidemia
GLYCOLYSIS where is it?
cytosolic
How do tissues use the glucose
•main nutrient for brain, RBC and tissues with low mitochondria
Glycogenolysis
liver
- rapid degrad
for blood gluc homeo
M
- rapid response to M E for contraction
- after heavy exercise, glycogen usually lasts ~4 hrs
- •Usually ~20 mile mark:”hitting the wall”
- FA becomes source of EL 130 ATP @ C16
quick response to glucagon/epi
Hematopoietic Stem Cell Transplantation
−Allows individuals to produce endogenous enzyme
−Recommended for MPS I (H, H/S)
Diabetic Ketoacidosis
PDHC deficiency and its pathway effect
Because pyruvate does not proceed to Acetyl-CoA, it is shunted to other pathways that produce lactic acid and alanine
FA oxidation occurs
•in the matrix of mitochondria
What is the consequence of Lactic Acidosis by Hypoxic cells?
1.Lactate –> exported
- •pHi alkaline
- •pHe acidic
- Increase in HIF-1a = increase in angiogenesis for tumor
- Lactate has immunosuppresive role
- T-cell proliferation
- cytokine production
- cytotoxic activity of CD8+ cells (tumor infiltrating lymphocytes)
•Fructose more or less sweet than sucrose
sweeter: •173 vs 100 Sweetness value
Main sources of sucrose
- beet or cane, high fructose corn syrup, fruits, and honey.
- 10% of Western diets
Importance of Glutathione
- Removing ROS from cells (especially Red Blood Cells)
- Maintains reduced state of –SH groups in proteins
- preventing their oxidation to S-S –> Denaturation –> Heinz bodies that attach to RBC membranes
•Prevents oxidation of membrane proteins in RBC and prevents deformability
- leads to enlarged spleen
Bile Salts
derivatives of cholesterol - made in liver
- Conjugated to glycine or taurine (a sulfated, nonproteinogenic amino acid)
- Needed for absorption and transport of fat-soluble vitamins
- Only significant way to remove cholesterol from body is via bile salts
bile salts = deprotonated bile acids (pka 2-4)
Fabry Disease
- Defects in α-galactosidase A
- Pain in hands and feet
- Inability to sweat
- clusters of small, dark red spots on the skin (angiokeratomas)
- Corneal opacity, hearing loss
- Progressive heart and kidney damage
- Enzyme replacement therapy available
Cytochrome P450 (CYP)
ØCYP is a “superfamily” of related Heme containing enzymes
ØIncorporate 1 atom of O into a substrateà OH
1 atom of O into H2O
R-H +O2+NADPH + H+à R-OH + H2O + NADP+
(R= Xenobiotic (toxins),Steroid, Bile Acid, Vit D)
ØProduct is more polar and more soluble: can be excreted(especially drugs and toxins)
ØNADPH is needed as reducing equivalent
Desaturases
•located in the ER
Lipids solubility
- Relatively insoluble in water
- Soluble in non-polar solvents (e.g., chloroform, ether)
Bile
watery mix of organic and inorganic cmpds
organic cmpds: lecithin, cholesterol, bile salts
bilirubin: catabolite of Hb
•Released from gallbladder in response to cholecystokinin (produced from lower duodenum and jejunum) and aids in emulsification, digestion and absorption of lipids
Sorbitol Metabolism: DM
hyperglycemia = increase [sorbitol] due to high [gluc] = increase osmosis = swell retina, lens, N
peripheral N-pathy
diabetic retinopathy
macular edema –> poor vision
Ketone Body Metabolism location?
- Made only in hepatic mitochondria
- Liver lacks thiophorase and so, cannot catabolize ketone bodies
Eicosanoids*
*The 2-series, derived from arachidonate, are the most abundant eicosanoids
Summary of Hormonal
Regulation of Lipolysis
•Importance of Succinyl-CoA
- Used to make Heme (Hb, Cytochromes)
- High energy-thioester –> hydrolyze –> GTP
Fructose Metabolism pathway
Regulation of Acetyl CoA Carboxylase (ACC) is what kind of regulation?
Allosteric
- ACC is inactive as a dimer and active as a polymer
- Citrate promotes polymerization of ACC
- LCFA-CoA inhibit the active polymer formation
Pyruvate
Major Biochemical Intermediate
- Makes Acetyl-CoA via PDHC
- Makes Alanine via ALT
- Makes Lactate via LDH
- Makes Oxaloacetate via Pyruvate Carboxylase
•Why are both hexokinase and glucokinase needed for glycolysis?
normal 5mM [Glucose]
- hexokinase (Km=0.1mM) phosphorylates glucose for metabolism.
blood glucose levels rise
- hexokinase is saturated
- glucokinase (Km=10mM) will become active to help prevent hyperglycemia.
Compounds that produce Acetyl-CoA are NOT gluconeogenic but are called
ketogenic
FA Synthesis - Termination
•When the FA chain length on ACP-SH reaches 16 carbons, intrinsic Thioesterase I activity of FAS releases the palmitate
•
- In lactating mammary epithelial cells, Thioesterase II – a discrete cytosolic protein – hydrolyzes shorter chain length FA (8-12C) from FAS complex
- For infants, shorter chain FA in mother’s milk are easier to digest
NO Synthase pathway
NO is important vasodilator of smooth muscle
NO –> (+) GUANYLATE CYCLASE -> INCREASE Cgmp –> ACTIV Protein kinase G –> P Ca2+ chann –> decrease in Ca2+ txp –> decrease in Ca2+ dependent MLCK –> inactiv smooth M contraction = dilation
Role of Bile Salts in Lipid Absorption
lipids have little solubility of H20 (minimal polarity)
increase [monomeric lipids] avail for absorption via micelles/vesicles
Unstirred water layer
•Acetone gives breath a _____ odor
“fruity”
Regulatory Enzymes in Glycolysis :
Irreversible Steps
- Hexokinase
- PFK-1*
(Phosphofructokinase-1) – rate-lim step
- Pyruvate Kinase
ROS Damage on proteins
- oxidation of a.a. side chains
- protein cross-linking
- protein fragmentation
MPS-II Hunter Syndrome
iduronate sulfatase deficiency
x-linked
coarse features, hepatosplenomegaly
no corneal clouding! (how to diff from MPS-I)
Why does the Malate-Aspartate shuttle produce 3ATP/NADH while the Glycerol 3-P shuttle only 2 ATP/NADH?
- Malate-Aspartate Shuttle feeds NADH into Complex 1 of ETCà 3ATP/NADH
- Glycerol 3-P Shuttle converts the NADH into FADH2 which feeds into Complex II of the ETCà 2ATP
A 2-year old boy presents with hypoglycemic coma which rapidly responds to intravenous glucose infusion. During the coma his blood glucose was 25 mg/dL (normal = 70-110 mg/dL) and bicarbonate was 13 mEq/L (normal = 24 mEq/L). Plasma and urine analysis showed very high levels of glycerol. The patient had normal adrenal function and no myopathy. These findings are best correlated with a deficiency of which of the following enzymes?
A.Aldolase
B.Glyceraldehyde-3-P dehydrogenase
C.Glycerol kinase
D.Gycerol-P dehydrogenase
E.Glycerol-P acyltransferase
A.Glycerol kinase
ROS: Reactive Oxygen Species:
danger of H2O2= ready conversion to the reactive hydroxyl radical (OH-)
- attacks memb = deform cytoskel = lysis = lemolytic anemia
- either by exposure to UV
- by interaction with transition metal ions
e.g. Fe, Hb Fe+2—>Fe+3 +e-, H2O2 + e- —> OH.
most common cause of PDHC Deficiency
X-linked E1 alpha gene
Fructose Metabolism vs Glycolysis
In liver: (Main fructose metabolizing organ)
- Not in skeletal muscle, adipose, RBC
Bypasses PFK-1
Fructokinase (low Km for fructose) –> F1P
Aldolase B –> Glyceraldehyde and DAHP = less ATP made using this pathway
- only DHAP can continue as G3p
- Glyceraldehyde needs to be converted using Triose kinase –> G3P
Among steroids, lipoxygenase inhibitors, and LT receptor antagonists, which would you predict to have fewest side-effects and why?
LT receptor antagonists are the most specific of the group and are expected to have the fewest side effects. Steroids block the formation of all eicosanoids and lipoxygenase inhibitors block the production of all LT as well as HETE.
Phase 2 – Activated 2-Carbon Units
- The committed and rate-limiting step of FA synthesis
- Activated by citrate, insulin
- Inactivated by LCFA, PUFA, glucagon, epinephrine, AMP
fat-soluble vit
adek
thromboxane A2 (TXA2):
•promotes platelet aggregation and vasoconstriction in arterioles
produced by platelets
Pyruvate Carboxylase
in mitochondria
Formation of OAA from Pyruvate
anapleurotic reaction: replenishes OAA
Acetyl-CoA: an allosteric activator
Energy required: ATP
Biotin deficiency(rare) could affect gluconeogenesis
a-Ketoglutarate DH(aKGDH)
- NADH, CO2
- High energy succinyl-CoA: importance =
- Used to make Heme (Hb, Cytochromes)
- can hydrolyzed –> GTP
•aKGDH (parallel to PDH complex)
- Complex:3 Enzymes and 5 cofactors
- Also inhibited by Arsenic: lipoic acid
Ethanol Ingestion Inhibits
GNG b/c….
large [NADH]
- LDH: Pyruvate +NADH –> Lactate +NAD+
- Malate DH: OAA +NADH –> Malate +NAD+
- Decrease in Precursors for Gluconeogenesis
Low blood glucose–>rapid heart beat
Increase in Lactate (metabolic acidosis) –>hyperventilation (respiratory compensation)
PDH Complex (PDHC) enzymes and cofactors
- 3 Enzymes: E1,E2,E3
- 5 Cofactors needed from vitamins:
–TPP (Thiamine pyrophosphate): Thiamine (Vit B1)
–FAD+: Riboflavin (Vit B2)
–NAD+: Niacin (Vit B3)
–Coenzyme A : Pantothenic Acid (Vit B5)
–Lipoic Acid
Prostacyclin vs Thromboxane
Aspirin and NSAIDs may promote gastric bleeding and lead to ulceration. COX2 specific drugs are safer for the stomach but may increase the risk of cardiovascular events by promoting thrombosis. So, what is the choice of pain medication for patients at risk of gastric bleeding?
A combination of a COX2 selective drug and low dose aspirin (or picotamide) to treat pain and keep the balance between prostacyclin and TXA2 levels.
During hypoxia, ______ cannot be reconstituted in mitochondria and its hydrolysis leads to ___________.
what is normal?
atp
- With an adequate supply of oxygen, the cells use ADP, Pi, and H+ in the mitochondria to reconstitute ATP.
accumulation of H+ and Pi in the cytosol
- ATP –> ADP + Pi + H+
lactate accumulation due to inab pyr to continue metab in mito
What Can Impair Lipid Digestion/Absorption?
•Pancreatic insufficiency
- −CF
- −Panc ca
•cholestasis
- Decreased bile flow usu due to Gall stones
•Inflammatory bowel diseases
- −Celiac sprue (gluten sensitivity)
- −Crohn disease (autoimmune)
- −Bowel resection
lactate-to-pyruvate ratio
is normally
25:1
what is the precursor of FA?
what is first made?
Acetyl CoA
- Palmitic acid (16:0) is first made
- All other FA made from palmitoyl CoA
−By elongation
−By desaturation
Aspirin
- irreversibly blocks COX 1 and 2
- Analgesic, anti-inflammatory and antipyretic
- Inhibits the production of both PG and TX
Asthma/Allergy Treatment
- Zileuton(Zyflo®), a 5-lipoxygenase inhibitor (will inhibit production of LT as well as 5-HETE)
- Pranlukast (Ultair®), Zafirlukast (Accolate®), Montelukast (Singulair®) are CysLT receptor antagonists
- Steroidal anti-inflammatory drugs like hydrocortisone, prednisone, and betamethasone, appear to act by blocking LT and HETE production by suppressing phospholipase A2 activity and interfering with the mobilization of arachidonic acid, the substrate for lipoxygenases
Sugars Need To be Activated
•Catalyzed by distinct glycosyltransferases specific for each sugar
NDP-Sugar + Protein → Protein-Sugar + NDP
Two Sources of NADPH
- Hexose monophosphate shunt (PPP)
- Malic enzyme
The use of NADPH by a Phagocytic cell
Allosteric Regulation of Glycogenolysis in Muscle: AMP
: Low energy
- AMP activates glycogen phosphorylase b WITHOUT phosphorylation by PKA
- Low O2/energy ,muscle can still undergo glycogenolysis àATP
Use of NADPH by Cyto P450
ØMitochondrial hydroxylation reactions of substrates
- Hydroxylation of steroids
- Mitochondrial Cyto P450
- Steroid producing organs, placenta, ovaries, testis, adrenal cortex
- Bile acid synthesis: liver
- Hydroxylation in Vit D synthesis: kidney
ØMicrosomal hydroxylation reactions: detoxification of toxins, drugs
Ø
Digestion of Cholesteryl Esters
via pancreatic cholesterol esterase into cholesterol + FA
free colesterol absorbed in duodenum and jejunum with NPC1-L1 txpor protein
•Prostaglandins
- promote inflammatory responses
- Individual PGs may promote (e.g., PGE2) or inhibit (e.g., PGI2) contraction of certain smooth muscles by interacting with different receptors
- Catalase (CAT)
ØPresent in peroxisomes in almost all cells
ØRemoves H2O2 without producing free radicals
FA classification based on chain length
Short chain FA (SCFA) < 6 carbons
Medium chain FA (MCFA) 6-12 carbons
- lactating mamm glands = easy to digest for infant
Long chain FA (LCFA) 14-22 carbons
Very long chain FA (VLCFA) > 22 carbons
- 34 in CNS, partic in myelin
Gluconeogenesis purpose
•synthesize glucose so as to maintain blood glucose levels within fasting range of 70-110mg/dl (~5mM)
Increase in Lactate Synthesis happens when
rate pyr form > rate of use by mito
- due to rapid inc in metab rate
- o2 delivery to mito declines = hypoxia
rate gluc metab > ox capacity of mito
- admit of catecholamines (epi)
- errors in metab
Tay-Sachs Disease
- Carrier rate is 1 in 30 among Ashkenazi Jewish population
- Defect in Hexosaminidase A
- Buildup of ganglioside GM2 in nerve cells
- Profound mental and physical retardation
- Cherry red spot on macula
Peroxisomal α-oxidation of Phytanic acid
- Produced from chlorophyll and a component of dairy products and some fish
- Oxidation of α-carbon produces pristanic acid
- •2,6,10,14-Tetramethylpentadecanoic acid
- •Can be metabolized by β-oxidation
final product of anaerbic glycolysis?
lactate
PPP
• Divided into 2 parts:
–Part 1: Oxidative reactions: Irreversible
–Part 2: Nonoxidative: Reversible
- No ATP used or made
- Present in all cells
- Cytoplasmic
Lactate Dehydrogenase
(LDH):
Conversion of
Pyruvate to
Lactate under
Anaerobic
Conditions
phospholipase c
live lysosomes, alpha-toxin of clostridia and other bacilli
PIP2 system = producing second messengers
•Acetyl CoA carboxylase: Regulation of FA Synthesis
- Short term regulation
- Allosteric regulation (citrate, LCFA)
- Covalent modification (glucag, ins)
- Long term regulation
- Gene expression
- High carb/low fat diet (↑)
- Fasting or High fat diet (↓)
Galactose Metabolism
Lactose Intolerance:
ØLactase deficiency: Primary
- Presents with diarrhea, bloating, cramps
- Can increase with age
- More than three quarters of the world’s adults are lactose intolerant
- Can vary within different ethnic populations
- 90% of adults of Asian or African descent
- 25% of Northern European descent (e.g. Dutch, Scandinavian)
- Up to 75% of the world population has some lactose intolerance
ØLactase deficiency: Secondary
- Due to intestinal injury
- First activity lost and last to recover
•Which GSD leads to Abnormal Glycogen structure?
- Andersen:Type IV: loss of branching
- Cori:Type III: loss of debranching
I-Cell Disease presentation
•coarse facial features, skeletal abnormalities, mental retardation and heart valve and respiratory problems
Glycogen Synthase types of regulation
ØAllosteric : + Glucose 6-P
ØCovalent: - dephos/+phosph via hormonal regulation by glucagon/insulin
1st Steps in Gluconeogenesis: 1st Bypass of Pyruvate Kinase
pyr -(pyr carboxylase)- oaam -(malate DH)- malatem - malatei -(malate DH)- oaac -(PEP carboxykinase) - pep
Precursors of Eicosanoids
Nitric Oxide: bactericidal
- NO + ROS –> OH·
- iNOS is induced by bacterial lipopolysaccharides and gamma-interferon released during infections
Heparan sulfate
cell surfaces, basement membranes
Hers disease
Type VI
•Liver phosphorylase deficiency
ØUsually only partial: complete would be fatal
ØExtreme hepatomegaly
ØHypoglycemia milder than in Type Ia
Glycosphingolipids characteristics
- Essential components of all membranes
- Located on the outer leaflet of the plasma membrane
- Found in greatest amounts in nerve cells
- Are antigenic: the carbohydrate portion being the antigenic determinant (e.g., blood group antigens)
- Can serve as cell surface receptors
•What is the connection between NADPH, G6PD deficiency and hemolytic anemia?
- G6PDH is an enzyme in HMPS that produces NADPH
- A deficiency in NADPH, especially in the RBC, prevents the reduction of glutathione to GSH which then prevents the removal of H2O2 by Glutathione Peroxidase (which requires GSH)
- H2O2 can attack RBC=lysis=hemolytic anemia
Hexokinase/Glucokinase
ØPhosphorylation effectively traps glucose in cell
ØReaction is irreversible
Primary carnitine deficiency
•Primary carnitine deficiency
- •Nutritional (e.g., Vegans)
- •Carnitine transporter defects
- •Hepatic synthesis defects
- •Renal reabsorption defects
- •Mild to severe muscle cramps and weakness
Warburg Effect
stats of glucose?
tumor cells use glycolysis to make lactate as its main metabolic pathway even in the presence of oxygen
•Up to 90% of glucose –> lactate (up to 40X more than normal)
LACTIC ACIDOSIS via LDH
Chondroitin sulfate
cartilage, tendon, bones
Exo-glycosidase Deficiency Diseases
β-Oxidation
mitochondria
- Major pathway (
- Mitochondria in liver, muscle
- Involves oxidation of β-carbon to release acetyl CoA
GSD 0: L
liver
- shows in infancy
hypoglycemia after long periods of fasting
- ketosis due to fat brkdown to acetyl-coa
- improves with eating
–Mutation in GYS2 gene: autosomal recessive
Mr. B is 69 yr old and presents with lethargy, headaches, frequent thirst and urination. His blood lab tests show:
ØGlucose (fasting):220 mg/dl (normal range: 65–109 mg/dl)
ØA1C: 8.1% (normal: 4–6%)
ØUrine: + for Glucose
What is going on?
§hyperglycemic
§High HbA1c
§Positive for glucose in urine
§Diagnosis: Diabetes Mellitus Type II (Adult)
Cardiolipin
- Two molecules of phosphatidic acid linked together covalently through a molecule of glycerol
- Acidic phospholipid found in inner mitochondrial membrane and in bacteria
- Anti-cardiolipin antibodies have been detected in anti-phospholipid syndrome (APS), syphilis infection and in systemic lupus erythematosus
•
Zellweger Syndrome
spectrum of disorders in the biogenesis of peroxisomes.
Viagra
Sildenafil
corpus cavernosum of the penis
inhibits the breakdown of cGMP(inhibits phosphodiesterase, PDE5) so that high levels of cGMP remain = high levels of vasodilation = ERECTION!
Odd-chain fats on gng
Øsuccinyl-CoA –> TCA intermediate –> OAA –> Gluconeogenesis
secretion of _______ in MPS VII
HS, CS, DS
sly syndrome: beta-gluconronidase
DS: Dermatan Sulfate; HS: Heparan Sulfate; KS: Keratan Sulfate; CS: Chondroitin Sulfate
Desaturation =
formation of double bonds
hypoglycemic effects of etoh
fasting, insulin intake, gng impairment = hypoglycemia
- agitation, impaired judgment, combativeness
•Heavy drinkers with no food deplete their glycogen stores within a few hours.
Cholestasis is a disease in which the flow of bile from gallbladder to the intestines is blocked (e.g., due to gallstones), leading to jaundice. The absorption of which of the following dietary components may be defective in cholestasis?
A.Thiamine
B.Octanoic acid (C8-fatty acid)
C.Vitamin K
D.Fructose
E.Vitamin C
●
Vitamin K
Synthesis of Glycerol 3-P: in liver
- Liver
- From DHAP
- Glycerol-P-dehydrogenase
- Requires NADH
- From Glycerol
- Glycerol kinase
What happens to glycogen stores under the fed state?
Increase in insulin leads to activation of Glycogen Synthase
Uses of NADPH (5)
- Reductive Biosynthesis
* •Fatty Acids - Combat Oxidative-Stress: ROS
- •Reduction of Hydrogen Peroxide
- •Reduction of Glutathione
3.Use of Cytochrome P450: MEOS,
steroids, bile acids, vit D,detoxification of xenobiotics
- Phagocytosis of bacteria by white cells
- Synthesis of Nitric Oxide:NO synthase
Infant respiratory distress syndrome (IRDS) is a disorder of the newborn. It is the result of insufficient production of lung surfactant, leading to fetal lung immaturity and atelectasis. Which of the following species represents the majority of the phospholipid in the lung surfactant?
A.Phosphatidylglycerol (PG)
B.Phosphatidylinositol (PI)
C.Phosphatidylcholine (PC)
D.Phosphatidylethanolamine (PE)
E.Phosphatidylserine (PS)
A.Phosphatidylcholine (PC)
Activation of FA to Acyl CoA
- Acyl CoA synthetase located in ER, outer mitochondrial membrane and peroxisomal membrane
- Reaction consumes an equivalent of 2 ATP
- Long chain acyl CoAs cannot cross inner mitochondrial membrane
Jamaican Vomiting Sickness
Consumption of unripe fruit of Ackee-Ackee Tree (native to West Africa, introduced to Jamaica in 1776)
Due to Hypoglycin A (Toxic amino acid)
- •Metabolic products sequester carnitine and CoA
- •Inhibits β-oxidation of fatty acids
If ingested
- •Sudden onset of vomiting (Within 2-6 hrs)
- •Severe Hypoglycemia
- •Generalized weakness, altered consciousness, and death
secretion of _______ in MPS II
DS, KS, HS
Respiratory Distress Syndrome
- The ratio of lecithin:sphingomyelin increases sharply during weeks 31-34 of gestation
- A ratio >2 in amniotic fluid is indicative of fetal lung maturity
- Surfactant biosynthesis is hormone regulated (corticosteroids, thyroxine, catecholamines)
- Insufficient DPPC synthesis leads to infant respiratory distress syndrome (IRDS)
- Dexamethasone is administered to mother shortly before delivery if fetal lung immaturity is suspected
- A deficiency of surfactant in adult lungs causes adult version of RDS (ARDS)
Glycogenolysis
- Not reversal of Glycogen Synthesis
- Cytosolic enzyme reactions
- Primary product: Glucose 1-P from a 1-4 linkage
- Glucose 1-P à Glucose 6-PàERà free Glucose in liver for blood glucose homeostasis via G 6-Ptase
PL (phospholipids) are mainly digested by
•pancreatic phospholipase A2 (activated by trypsin)
ABO antigens may be attached
to both proteins and lipids on the surface of red blood cells
G6PD deficiency can be triggered by
stress on systems need for detoxification
- infection(most common)
- Excess physical activity
•fava beans(favism)
mothballs
Mucin (shown below) is a gastric membrane protein that is ~80% carbohydrate. It consists of a core protein in which multiple oligosaccharides are attached to Ser/Thr residues. Mucin is an example of which of the following classes of molecules?
A.N-linked glycoprotein
B.O-linked glycoprotein
C.Proteoglycan monomer
D.Proteoglycan aggregate
E.Glycosaminoglycan
O-linked glycoprotein
Eicosanoid
- Mostly derived from the 20-carbon poly-unsaturated fatty acid, Arachidonic acid (5,8,11,14-eicosatetraenoic acid)
- Paracrine (Target = adjacent cell types) or autocrine (Target = same cell type) messenger molecules (“local hormones”)
•
•Short half-lives (10 sec – 5 mins) (exception: Prostacyclin)
I-Cell Disease
mucolipidosis
autosomal recessive - multiple acid hydrolases missing from lysosomes: secreted and found in plasma
- no addition of phosphates to N-linked mannoses on enzymes destined for lysosomes
large inclusion bodies in cells
defect in sorting of proteins destined for lysosomes
BMT = only tx option
Thiamine as a Cofactor in which kinds of rxns? what are they?
Decarboxylation Reactions
- PDH : E1 Pyruvate decarboxylase àCO2
- a-KG DH:E1àCO2(TCA)
- Transketolase: transfer of 2C units(PPP)
- Branched chain a-ketoacid DHà CO2(A.A.)
•Secondary carnitine deficiency
- Accumulation of acyl carnitines due to CPT-2 or CACT defects
- Acyl carnitines inhibit renal resorption of carnitine
- Treatment
- High carb/low LCFA diet
- Increase MCFA content in diet
- Limit physical activity
- Carnitine supplements
products of TCA cycle
- 6C -> 5C -> 4C
- 2 CO2
- Energy:
- 3NADH -> 3x3 ATP =9ATP
- 1 FADH2 -> 1x2 ATP =2ATP
- 1GTP =1ATP
- Total= 12ATP/cycle
Prostacyclin (PGI2)
- Vasodilator, Bronchodilator
- Stabilizes platelets, disaggregates platelets
- Produced by blood vessel wall
The three most abundant phospholipids in humans
precursor?
Malate-Aspartate Shuttle
1.Preferred shuttle in liver, heart and kidney
3 ATP can be generated
Eicosanoid Biosynthesis: pathway
ROS dmg on DNA
ØMain oxidative product:
ØOxidizes guanosine à8-hydroxydeoxyguanosine
ØMutations and carcinogenesis
UDP-Glucose: how is sugar added?
Sugar always added to the non-reducing end via UDP-sugar
Use of Ribose 5-P
Precursor for nucleotide synthesis
•Ribulose 5-P –> Ribose 5-Phosphate via isomerase Ribose 5-P –> PPRP –> Purines and Pyrimidines
(ATP, GTP, CTP, UTP, TTP)
specific enzyme missing from I-cell disease
glcnAc-!-P phosphotransferase –> failure to target lysosomes and defult secretion of n-linked mannoses
Regulation of PFK-1: hormonal
- insulin
- MAIN + REGULATOR OF GLYCOLYSIS
- high glucose = inc f (2,6)bp = increase pfk-1 = increase glycolysis
- glucagon
* low glucose = dec f (2,6)bp = dec pfk-1 = dec glycolysis = incrase GNG
Sphingomyelin
The only significant sphingophospholipid in humans
Important constituent of myelin (18% protein and 76% lipid)
Myelin sheath insulates and protects neuronal fibers
Sphingomyelin is usually associated with the cholesterol in the membrane
Glycosphingolipids types
•Cerebrosides: Ceramide + 1 or 2 sugars
- •Glucose or galactose
- Sulfatides: Ceramide + 1 sulfated sugar
- Globosides: Ceramide + ≥3 sugars with an N-acetylated sugar
- Gangliosides: Ceramide + 3 or more sugars with sialic acid (NANA)
mps II: Hunter Syndrome
normal eye - no corneal clouding
increase concentration of gag in urine
iduronate sulfatase deficiency
hepatosplenomegaly
x-linked
How does Glucagon help to maintain blood glucose homeostasis?
secr from panc α-cells
inhib production of f(2,6)bp
=pfk-1 inhib = bypass rn from f(1.6)bptase (+) = gluc prod = blood gluc homeostasis
DGAT expression is induced by…
- insulin
- DGAT is being evaluated as a pharmacological target in the treatment of obesity
Phosphofructokinase-1 (PFK-1)
Most important control-point in glycolysis
- rate-lim and commited
irreversible under physiological condition
consumes 1 ATP
GAG Degradation
endo-β-glucuronidase first cleaves large chains into smaller fragments
each monosacc removed from nonreducing end
•N- and O-sulfate groups must first be removed before exoglycosidases can act
Why does the complete catabolism of one mole of glucose produce 38 ATP in the liver but only 36 ATP in skeletal muscle?
liver = malate-asp shuttle - 6 atp
skeletal M = g3p - 4 atp
Glucose to Sorbitol enzyme
Aldose Reductase
α-Oxidation
- (peroxisomes)
- Minor pathway, no energy yield
- Phytanic acid (branched)
Glycerol as a Gluconeogenic Precursors
Glycerol - Glycerol 3-P - Glyceraldehyde-3-P ——– GLUCOSE
Heparin found in
intracellular granules in mast cells
Gaucher Disease
- Most prevalent lysosomal storage disease
- Defective glucocerebrosidase (β-glucosidase)
- Gaucher cells most often accumulate in bone marrow, spleen, and liver
- Leads to hepatosplenomegaly (macrophages prominent in liver and spleen), osteoporosis
First disease to be treated with enzyme replacement therapy
Phosphatidylinositol
ex of glyverophospholipid
inositol as polar head group
memb lipid, cell signal
Lactose
Synthesis
protein A and B
- A = usually used to synth N-linked glycoproteins in most tisuses except lactating glands
- B only in lactating mamm glands - stim by prolactin
- Produced by mammary gland
- Under hormonal control
Membrane Lipids
phospholipids, cholesterol, glycolipids
−Amphipathic lipids
−Both nonpolar and polar groups
Fumarase
•Forms Malate using H20 (Hydration)
malate-aspartate shuttle
- bring NADH into mito
malate –> pyr + NADPH (important for lipid synth)
malate <—> oxaloacetate
Niemann-Pick Disease
•Niemann-Pick disease Type A and B
–Autosomal recessive lysosomal storage disorders
–Deficiency of acid sphingomyelinase
–Type A (Less than 1% normal activity):
- Death by age 2 or 3
- Hepatosplenomegaly - Sites of lipid deposit; Also CNS (ataxia, seizures)
–Type B (5% or more activity) - Less severe
- •Bone marrow and stem cell transplantation therapies have been useful for treating type B
•Type C
- disease due to the absence of sphingomyelin transporters
What is the difference between Anerobic glycolysis and Aerobic glycolysis? Isn’t all glycolysis the same pathway?
anaerobic:
- when no ox path available
- no mito in RBC
anerobic:
- ox path avail, but cell chooses lactic acid as end product
- common in malignant cells
glycolytic rxn are same BUT:
- different isoforms inc, diff enz kinetics, diff signal paths
ØType IIA (intermediate)
intermed of type IIB and I
aero and anaero
“normal m”
Polyunsaturated Fatty Acids (PUFAs) are formed through…
a combination of elongation and desaturation
•Types of FA synthesized
−Saturated
−Unsaturated (D4, D5, D6, D9)
−Odd chain (minor)
−Branched (minor)
A 6-year old boy presents at the clinic with coarse facial features, mental retardation, abnormal bone development and a milky cornea. Urine analysis reveals elevated levels of dermatan sulfate and heparan sulfate. The child is likely to be suffering from which of the following disorders?
A.I-cell disease
B.Sly syndrome
C.Sanfilippo B syndrome
D.Hunter syndrome
E.Hurler syndrome
Hurler syndrome
TCA Cycle is the source of…
- most of the energy in your body
- All of the food you eat: carbohydrates, fats, proteins all end up in some form in the TCA cycle
Lipids major func
−Major storage form of energy
−Membrane structure and function
−Cell signaling
−Insulation
•Sources of carnitine
- Mainly diet – meat
- Limited synthesis in liver and kidneys from lysine and SAM
- Heart & skeletal muscle cannot make carnitine but have high affinity uptake
Formation of Acyl carnitine
Secretin
prod by S cells in duodenum
response to chyme acidity
func:
- pancreas: secr bicarb
Sphingolipidoses
•Lysosomal storage disorders
Cytochrome P450 Reductase
- Part of an electron transport chain found in the endoplasmic reticulum.
- P450 interacts with NADPH-cytochrome P450 reductase, a flavoprotein that is necessary for the transfer the reducing equivalents to Cyt P450.
- Other proteins that interact with Cyt P450: cytochrome b5, NADH-cytochrome b5 reductase, and heme oxygenase.
ATP production from 1mole Glucose
Cori Cycle:
•Lactate
–Anerobic metabolism in Skeletal muscle, RBC etc.
–Cori cycle recycles Lactate from muscle to liver for gluconeogenesis
–LDH converts LactateàbloodàPyruvateàGlucose
Regulation of CPT-1
- ACC converts acetyl CoA into malonyl CoA
- Malonyl CoA inhibits CPT-1
- AMP (low energy) inhibits ACC and stimulates the breakdown of malonyl CoA to acetyl CoA
•Lipoxins, Resolvins, and Protectins may be produced at lower than normal levels in chronic inflammation
TAG Synthesis
Succinate Dehydrogenase
FADH2 –> Complex II
- Functions as part of Complex II of ETC
loc: inner mito membrane
Flavo protein
β-Oxidation of FA
Phase II
•Each cycle has:
- •Oxidation
- •Hydration
- •Oxidation
- •Lysis
- Separate acyl CoA dehydrogenases (SCAD, MCAD, LCAD, VLCAD)
- Each cycle yields 1 FADH2, 1 NADH and 1 acetyl CoA
- Deficiency of MCAD causes hypoglycemia
Sorbitol
Metabolism:
Polyol
Pathway
Seminal Vesicles, liver,ovaries
Aldose Reductase –> Sorbitol (NADPH + H –> NADP+)
- •Sorbitol DH –>Fructose (NAD+ –> NADH + H)
- way for the body to produce fructose from glucose without using ATP
- Fructose: major E source
Lens, Nerve, Kidney:
- •Aldose Reductase –> Sorbitol (NADPH + H –> NADP+)
- •Low or absent Sorbitol DH
- •High [glucose] –> high[sorbitol] –> osmotic effects –> swell
Bypass of PFK-1:
ØImportant regulatory site
•Fructose 1,6-bisphosphatase
inhibited by high AMP
(low energy)
- Stimulated by high ATP
- Inhibited by F2,6bisP
- Stimulated by Glucagon:
- Decreases [F2,6bisP]
- Increases Gluconeogenesis
Energy Yield from One Palmitic Acid (16:0)
β-oxidation of odd-chain FA
- Last cycle of odd-chain FA oxidation yields propionyl CoA (3C)
- Propionyl CoA is metabolized to succinyl CoA via methylmalonyl CoA (needs vitamin B6)
- Deficiency of mutase or of vitamin B12 causes methylmalonic aciduria
- •Metabolic acidosis
- •Mental retardation
Role of G 6-P and its routes to pathways
Hexose Monophosphate Shunt (PPP): part 2
Part 2: Non-Oxidative, Reversible:
Main products:
Ribose 5-P: via Isomerase for nucleotide synthesis
Comparison of FA Synthesis & Degradation
Von-Gierke Disease
Glycogen Storage Disease Type 1a - most common
auto recessive - missing liver G6Ptase
symptoms:
- hypoglycemia, hepato-renal-megaly(enlarg), hyperlipidemia, hyperuricemia (high uric acid)
tx:
- no fasting!
18F-fluorodeoxyglucose (FDG)
–nonmetabolizable derivative of glucose preferentially taken up by tumor cells
•Can follow tumor treatment response using FDG-PET:
- Fluorodeoxyglucose-positron emission tomography
Superoxide dismutase(SOD)
ØManganese SOD (Mn SOD)- mitochondrial enzyme
ØSOD1:Copper-Zinc SOD(CuZnSOD) – mainly cytoplasmic but also found in lysosomes, peroxisomes,nucleus
ØDeficiencyàprogressive neurodegenerative disorder, Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig’s Disease)
ØALS: most have single pt-mutation (1a.a.)
ØExtracellular SOD(ECSOD)-uses Cu,Zn
Succinate Thiokinase
(Succinate Synthetase)
Cleaves high-energy Succinyl-CoA –> GTP (interconvert with ATP), CoA
Substrate–level phosphorylation
emulsification of fat
duodenum
increase SA of lipids
bile salts + peristalsis
- lipid particles = smaller, prevented from coalescing
Synthesis of Glycerol 3-P: adipose
- Adipose tissue
- Only from DHAP
- Glycerol kinase is absent in adipose tissue
Elongation of FA
- Palmitate is first activated to palmitoyl CoA
- Elongation occurs in smooth ER and in mitochondria
- Similar to FA synthesis
- Elongase uses either malonyl CoA (SER) or acetyl CoA (mitochondria) as the 2-carbon donor
- NADPH supplies the reducing equivalents
Nitric Oxide Synthase
Glycoprotein vs Proteoglycan
Phosphatidylserine (PS) is made by
base exchange
The repeating unit of a GAG
- Six classes of GAG based on the repeating unit (n = 100s to 1000s)
- Amino sugars may be Sulfated (on C4, C6 or on non-acetylated N)
- Five of the six classes of GAG are covalently attached to proteins (exception is hyaluronic acid)
FA Synthase Complex
- FA synthase complex contains 7 different enzyme activities
- The addition of each 2-carbon unit requires four steps:
- Condensation
- Reduction
- Dehydration
- Reduction
- The end product of FA synthase is the 16C FA, palmitic acid
- FA are synthesized from ω-end to α-end
Galactokinase deficiency
•(non-classical galactosemia)
Rare autosomal recessive disorder
- semia and galactosuria
- No Gal 1-P accumulation in tissues
- Galactitol accumulation
- Can lead to cataract formation
Carnitine Shuttle
Ethanol Metabolism
- 95% metabolized in liver
- Oxidation of Ethanol–> large [NADH]
Sites of Production of Major Prostanoids
Isocitrate DH
- NADH formed –> 3ATP
- Rate-limiting rx: exergonic
- Importance of a-ketoglutarate
- Interconverts with Glutamate via Glu DH:
- source of Glu or Glu = source of a-KG for TCA
Malate Dehydrogenase(MDH)
Forms NADH, OAA
endergonic
- driven forward by low [OAA] due to use in citrate synthase rxn
Gluconeogenesis:
Endergonic : Energy used
glycerate kinase and g-3-pdh = reversible rxns in glycolysis
IRREVERSIBLE : -G
Microsomal Ethanol Oxidizing System
increases after chronic alcohol consumption.
MEOS pathway requires the CYP2E1 enzyme, part of the cytochrome P450 family of enzymes
diff between O- and N-linked glycoproteins
Glutathione and Peroxide
G6PD Deficiency vs Sickle Cell Disease
General Structure of a Fatty Acid (FA)
Carboxylic acids with hydrocarbon chains containing between 4 to 36 carbons
Almost all natural fatty acids have an even number of carbons
Most natural fatty acids are unbranched
Cholecystokinin (CCK)
prod by I-cells n duodenum and jejunum
func:
- stomach: decrease gastic motility
- pancrease: secr panc enz
- gallbladder: secr bile
FA Synthesis – Rinse and Repeat
- FA synthase binds one acetyl unit and one malonyl unit
- A 2-carbon unit is transferred from malonyl unit to acetyl unit to form a 4-carbon unit
- The oxygen is replaced by hydrogens
- This process is repeated using new malonyl units a total of 7 times
Glucokinase(GK) Regulation
F6P –> Glucokinase regulatory protein (GKRP)–(+)–> bind Glucokinase –> nucleus
When [glucose]increases –> GKRP releases GK –> P glucose –>preventing hyperglycemia
GK only active under higher [glucose]
TAG Digestion entire pathway
citrate synthase
ØCoASH released
ØImportance of Citrate:
vShuttled to cytosolàAcetyl-CoA + OAA
- Acetyl-CoA used to make fat
- Citrate activates main fat synthesizing enzyme in cytosol
•
ØTake Away Point: SUGARS ARE FATTENING!!!!!!!
Chylomicrons
exogenous or diet-derived lipids
- ppl
- apolipoprotein B48 (from aa)
- TAG
- cholesteryl ester
deliver to muscle, adipose and liver via lymph sys
Synthesis of Lipoxins, Resolvins & Protectins
Nomenclature is similar to LT, PG, TX, and HETE:
- Lipoxin = LX
- Resolvin = Rv
- Protectin = P
- Capital letter designation of different forms
- Subscript = number of ‘non-ring’double bonds for LX
- AT =‘Aspirin-triggered’= different stereochemistry
•
Synthesized from:
- Arachadonic acid (C20:4, ω-6) - Lipoxins
- Eicosapentanoic acid (EPA, C20:5, ω-3) - E series Resolvins
- Docosahexanoic acid (DHA, C22:6, ω-3) - D series Resolvins and Protectins
Covalent Modification of ACC
•Phosphorylation of ACC promotes its depolymerization to inactive dimer
Allosteric Regulation of Glycogen Synthase
•Activated under well fed state by Glucose 6-Phosphate
- prod hexokinase/glucokinease
- in M and liver
g6p –> g1p
Glutathione activation
Peroxisomal beta oxidation of VLCFA
•First step catalyzed by acyl CoA oxidase, e- go to oxygen directly
what does Branching Enzyme do?
a 1,6 linkages
@ 6-8 residues
increase # sites for synth/degrad
increase # non-reducing ends avvail for degradation when needed
increases solubility
–Amylopectin has branches
–Amylose: straight chain: less soluble
Debranching Enzyme
Bifunctional
A.4:4 Transferase:
Transfers 3 glucose units to another branch to elongate
(all alpha 1,4)
B. 1:6 Glucosidase:
Single glucose left at branch site of a1,6 hydrolyzed
results in free glucose
Fatty Acids - saturation examples
Uridyltransferase deficiency
- Seen in homozygotes: need a reduction of > 50% of activity to see clinical symptoms
- Gal 1-P increases in tissues and Gal seen in blood and urine
- Mental retardation: need immediate treatment with infants
- Newborns ingest up to 1g galactose/day in milk
- Liver and kidney damage and cataracts
- Part of Newborn Screening Panel NYS
Why are 18C fatty acids (FA) like linoleic acid and α-linolenic acid considered as essential fatty acids?
A.Because humans cannot desaturate these FA
B. Because humans cannot synthesize n-6 (ω-6) and n-3 (ω-3) FA
C. Because humans make arachidonic acid from α-linolenic acid
D. Because humans make EPA and DHA from linoleic acid
E. Because humans cannot elongate 16C FA to 18C
. Because humans cannot synthesize n-6 (ω-6) and n-3 (ω-3) FA
Sugars entering Glycolysis/Metabolism
holy shit there is a lot
Type II GSD
(Pompe Disease)
By-Pass Reactions of Irreversible Reaction:
Glycolysis vs. Gluconeogenesis
Hexose Monophosphate Shunt (PPP)
PART 1 : Oxidative
- makes NADPH
•Glucose 6-P –> Ribulose 5-P + 2 NADPH
–Irreversible steps that produce NADPH:
- Glucose 6-DH(G6PD)*+ NADPH
- 6-Phosphogluconolactone hydrolase + NADPH
Glycerol 3-P Shuttle
operates in skeletal muscle and brain
MAX 2 ATP gen from each NADH produced in glycolysis
