Biochemistry Flashcards
Why is the energy yield slightly less from unsaturated fatty acids? (2)
- less FADH2 is produced
- may cost an NADPH (eq of 2.5 ATP)
- not hugely significant physiologically or energetically
What extra product is unique to metabolism of odd chain length fatty acids?
Propionyl CoA
How does the body get rid of propionyl CoA? (2)
Converts it to Succinyl CoA (also uses B12 as a coenzyme), which has 3 fates:
- replenish TCA cycle (oxidation to CO2 and H2O for energy)
- provide carbons for gluconeogenesis
What accumulates in the blood when someone is B12 deficient?
methylmalonic acid (because methylmalonyl CoA mutase - enzyme in propionyl CoA metabolism - is defective)
Where does fatty acid oxidation occur?
Mitochondrial matrix
Regulation of long chain FA synthesis/oxidation.
- NAD+/NADH ratio
- compartmentalization (FA oxidation in mito matrix separated from FA synthesis in cytosol by carnitine transport system)
What inhibits the carnitine, and why is this important?
- inhibited by malonyl CoA (intermediate in FA synthesis)
- prevents simultaneous FA synthesis and oxidation, which is just a waste of energy
Where is the peroximal pathway most active?
Liver and brain
What are the alternate routes of FA oxidation?
- peroximal: for VLCFA and branched chain FA; requires alpha-oxidation
- microsomal: for detoxification of hydrophobic xenobiotics; requires omega-oxidation
Zellweger syndrome
- defect in peroxisomal biogenesis
- accumulation of VLCFA in tissues; mainly affects liver and brain
- Sign: elevated C26:0 and C26:1 FAs in plasma
In order, what are the sources of glucose for the brain, and how long after a meal will they kick in?
- Recently ingested food (absorbed to blood from small intestine); i.e. when blood glucose is plentiful
- Glycogen breakdown (mainly from liver); begins at ~ 4 hours and stores last about 24 hours
- Gluconeogenesis (from muscle protein, glycerol from adipose, lactate from RBC, all sent to liver), starts at 4 hours and takes over for glycogen at about 16 hours
- Ketone bodies (made in liver from FA); begin production ~ 4 days into starvation
Where are insulin and glucagon produced, and when are they upregulated?
- glucagon: alpha cells of the pancreas; secreted when blood glucose is low
- insulin: beta cells of the pancreas; secreted when blood glucose is high
What are the two important ketone bodies?
- beta-hydroxybutyrate (tends to have much higher levels)
2. acetoacetate
What tissues use ketone bodies?
- brain
- adipose (switch to FA during prolonged starvation)
- muscle (switch to FA during prolonged starvation)
- heart (switch to FA during prolonged starvation)
- intestinal (switch to FA during prolonged starvation)
- fetal
Which tissues DO NOT use ketone bodies?
- Liver
2. RBCs (ketone bodies require aerobic metabolism)
What is the sparing effect of ketone bodies?
It stops the necessity of breaking down protein for fuel
What is the important clinical hallmark of diabetic ketoacidosis?
Acetone breath (fruity smelling)
What is the net rxn for the synthesis of one ketone body?
2 acetyl-CoA –> 1 acetoacetate OR 1 beta-hydroxybutyrate
Why can’t liver use ketone bodies?
It lacks the first enzyme (acetoacetate-CoA transferase) needed to oxidize ketone bodies.
What is the advantage of branching in glycogen storage?
- solubility (helps to prevent precipitation in cells)
- rapid degradation (more sites for enzymes to work)
What are the steps and enzymes in order to breakdown glycogen?
- Glycogen phosphorylase: phosphorylates the terminal glucose (G-1-P) and separates it from the chain
- Phosphoglucomutase: converts G-1-P to G-6-P
- Glucose-6-phosphatase: unique to the liver and kidney cortex, de-phosphorylates glucose so that it can diffuse from the liver into the blood stream
What is the enzyme and process of de-branching glycogen stores?
Debranching enzyme.
Glycogen phosphorylase is too sterically hindered to work once it reaches 4 glucose molecules away from a branching point. The debranching enzyme breaks the 1-6 bond of the shortened branch and makes a 1-4 bond to attach it to another straight chain. Glucosidase releases a free glucose. Glycogen phosphorylase can then take over.
What are the steps and enzymes in order to make glycogen?
- hexokinase/glucokinase: glucose taken up from blood and phosphorylated
- phosphoglucomutase: converts G-6-P to G-1-P
- UDP-glucose phosphorylase: adds a UDP group to glucose (provides E for next reaction)
- glycogen synthase: adds G-1-P to terminal end of a glycogen chain (1-4 bond)
Where does galatose enter the metabolic pathways, and what are the notable enzymes?
It is converted to G1P (then to G6P)
- galactokinase (galatose to galactose-1-phosphate)
- Galactose 1-phosphate uridylyltransferase (works with another enzyme epimerase to convert galactose-1-phosphate to G1P)
Where does fructose enter the metabolic pathways, and what are the notable enzymes?
Liver: It is converted to DHAP and GAP (eventually to pyruvate)
- fructokinase (fructose to F1P)
- aldolase B (F1P to DHAP and glyceraldehyde)
Can also be converted directly to glucose
What are major sources of fructose?
Sucrose (table sugar), fruit, corn syrup
What are major sources of galatose?
Lactose (dairy)
Which enzymes are reciprocally regulated in the glycogen synthesis/breakdown cycle, and how are they affected by activation of the protein kinase A cascade?
- glycogen synthase (synthesis); inactivated by phosphorylation
- glycogen phosphorylase (breakdown); activated by phosphorylation
What are general methods of reciprocal regulation?
- phosphorylation/de-phosphorylation (secs to hrs)
- allosteric activation/inhibition (secs)
- induction/repression (hrs)
A defect in Type I collagen gives what disorder?
Osteogenesis Imperfecta
A defect in Type III collagen gives what disorder?
Ehlers-Danlos type 4 (mesh-forming)
What problems are associated with Ehlers-Danlos syndromes, in general?
- aortic rupture
- GI tract
- pregnancy problems
- skin fragility
- poor wound healing (surgical problems)
What is the distinguishes collagen Type III vs Type I and II biochemically?
Type III contains disulfide bridges between chains
Describe the organization of the collagen polymers.
Primary: repeating Gly-X-Y sequence; lots of proline and hydroxyproline
Each chain forms a left-handed helix (Gly face inside); 3 of them wind together into a stretched right-handed superhelix (3 AAs per turn).
What is the defect in Ehlers-Danlos type VII?
Faulty aminoprocollagen peptidase, which is responsible for cleavage of the N-terminal globular domain to form tropocollagen.
Carboxyprocollagen peptidase cleaves the C terminal globular domain.
What is the defect in Ehlers-Danlos type VI?
Deficiency of lysyl hydroxylase, which is responsible for cross-linking the free (non-triple helix) ends of collagen fibrils.
What is the defect in scurvy, and the associated dietary concerns?
Deficiency of ascorbic acid, which is responsible for hydroxylation of proline residues on collagen.
Provided in part by intake of Vitamin C.
What are the cardinal clinical symtpoms of all Ehlers-Danlos syndromes? (3)
- easily bruised skin
- hyperextensible skin
- joint hypermobility
G6PDH deficiency
Drop in enzyme count for 1st (committed step) for pentose phosphate pathway.
- cannot regenerate NADPH
- cannot get rid of radicals (can’t regenerate glutathione)
- forms heinz bodies and RBCs will lyse
- decreased peroxidase activity
- heterogenous (in females) protects against malaria
- can’t take antimalaria meds
Von Gierke disease
Glycogen storage disease Type I
- deficient in glucose-6-phosphatase
- can’t send glucose out to blood from liver
- liver will swell
- convulsions
- low blood sugar, but increased lactate
What are common dietary sources of medium, long, and very-long chain fatty acids?
Medium: coconut oil
Long: leafy greens
V-Long: fish oil, plant oil (esp. peanut oil)
What carries fatty acids from adipocytes to other tissues?
Serum albumin
What is Refsum disease?
It is a defect in the alpha-hydroxylase enzyme of the peroxisomal pathway. They can’t break down VLCFA (esp branched). Phytanic acid will accumulate in the blood.
What is Andersen’s disease?
- glycogen storage disease Type IV
- defect in the branching enzyme for glycogen synthesis
- short, outer branches in glycogen
- cirrhosis, liver failure
What is Pompe disease?
- glycogen storage disease type II
- defect in lysosomal alpha-1,4-glucosidase
- causes cardiomyopathy
What is Cori disease?
- glycogen storage disease type III
- milder form of type I (von Gierke)
- defect in debranching enzyme (alpha-1,6-glucosidase)
- normal blood lactate levels
- gluconeogenesis is intact
What is McArdle disease?
- glycogen storage disease type V
- defect in skeletal muscle glycogen phosphorylase
- can make glycogen in muscle but can’t break it down
- muscle cramps
myglocinuria (red ruine) - arrhythmia from electrolyte abnormalities
With which disease are patients likely to have weakness as well as a “second wind”?
McArdle disease
What is the associated diagnosis for red urine with strenuous exercise?
McArdle disease
Ehlers-Danlos type 4
collagen type 3 deficiency. Easy bleeding and bruising
loss of function of lysylhydroxylase to hydroxylate lysine to hydroxylysine
Hunter’s disease
Lysosomal storage disease
- deficiency of iduronate sulfatase
- heparin sulfate and dermatan sulfate will accumulate in the blood
- X-linked recessive (more common in males)
Hurler’s disease
deficiency of A-L-iuronidase (2nd step) (glucosidase deficiency)
- autosomal recessive
- accumulation of dermitan and heparin sulfate in many tissues (brain, liver, heart)
- retardation, coarse facial features
- premature closure of growth plates
- macroglossia
- early death of respiratory failure
Mucopolysaccharidoses diseases
inability to degrade polysaccharide chains
Osteogenesis imperfecta
type one collagen deficiency. loss of triple helix structure and glycosylation. Brittle bones, fractures, hearing loss, blue sclera. Autosomal Dominant
Scurvy
loss of hydroxylation of collagen (loss of vit c/ascorbate corfactor for prolylhydroxylase); weakness, bleeding gums, poor wound healing
deficiency of vitamin c
loss of function of of prolylhydroxylase to hydroxylate proline
leads to scury
What are the steps of collagen synthesis? Which are intracellular/extracellular?
Intracellular:
- Synthesis of the Pro-alpha chain
- Hydroxylation of Prolene and Lysine (increases the melting temp)
- Glycosylation into triple helix
- Exocytosis out of cellular membrane
Extracellular:
- Proteolytic cleavage at the disulfide bridge terminals
- Cross-linking: lysyl oxidase catalyze lysine/hydroxylysine crosslinkage
What is the difference between osteogenesis imperfecta type I and II?
Type I is milder, normal lifespan; Type II is lethal.
- both are characterized by hearing loss, teeth and bone fragility
- both affect Type I collagen and are autosomal dominant
When is collagen degraded?
cell migration and tissue remodeling, rumor metastisis
What is the function of endostatin in collagen?
It’s a terminal peptide in certain types of collagen that inhibit angiogenesis, protects against invading cells
How does the structure of proteoglycans support the mechanical and osmotic function?
Structure allows it to be highly osmotic (holds water tightly, like a gel) which protects the cell and provides mechanical resiliency (shock absorbers)
