Mitsouras Flashcards
Allosteric regulation of enzyme activity
Reversible & transient effects; fast-acting and short-range
Covalent modification of enzyme activity
Reversible & transient effects; fast-acting and long-range
Hormonal control
Permanent effects; slow-acting and long-range
Gluconeogenesis
the synthesis of glucose from non-glucose precursors
Gluconeogenesis
the synthesis of glucose during starvation when liver glycogen stores are depleted
Which metabolic fuels are generated and how during the fed state?
Insulin: causes organs/tissues to uptake glucose;
mm and liver store excess
Which metabolic fuels are generated and how during the fasting state?
Glucagon;
glycogenolysis and gluconeogenesis in liver
Which metabolic fuels are generated and how during the starvation state?
Glycogen stores are depleted so gluconeogenesis is only source of glucose
How are FA and ketone body levels in circulation during fasting?
equal!
How are FA and ketone body levels in circulation during starvation?
more ketone bodies than FAs (ketone bodies left free in blood for brain)
Absorption of monosaccharides
From intestinal epithelium into circulation
Transport of monosaccharides
From circulation into cells
During what state does digestion of dietary carbohydrates result in increased blood glucose levels?
Fed state (about 30 min after a meal)
GLUT1
Tissues: Most cell types (RBCs, brain) but not kidney or SI
Function: Glucose & galactose transporter; High affinity; Basal glucose uptake ***** Low capacity
GLUT2
Tissues: Hepatocytes, pancreatic b-cells, SI & kidney
Functions: Glucose, galactose & fructose transporter; High capacity & low affinity; Glucose-sensor; Exports glucose into blood after uptake from lumen of SI**
GLUT3
Tissues: Most tissues/ organs (brain, testes, placenta)
Functions: Glucose & galactose transporter; High affinity; Basal glucose uptake **low capacity
GLUT4
Tissues: Skeletal muscle & adipocytes
Functions: Glucose transporter; High affinity; Insulin-dependent**
Imp in lowering blood glucose levels. Insulin increases number of receptors on cell-surface
GLUT5
Tissues: SI, sperm, kidney, brain, muscle, adipocytes
Functions: Fructose transporter; High affinity
GLUT7
Tissues: Membrane of ER in hepatocytes
Functions: Glucose transporter; Transports free glucose from ER to cytoplasm for release into blood by GLUT2 (during gluconeogenesis)
SGLUT1
Tissues: Epithelial cells of SI & apical surface of kidney tubules
Functions: Glucose, galactose co-transporter with Na+ (same direction); Uptake of sugar from lumen of SI against gradient, ATP Dependent
SGLT1 and SGLUT1: Na+Dependent Co-transporters
Anaerobic glucolysis
glucose –> 2 lactate, 2 ATP produce (no NADH)
Allosteric regulation of glucokinase
activated by glucose
Allosteric regulation of hexokinase
inhibited by glucose-6P
Allosteric regulation of PFK-1
inhibited by ATP, citrate
activated by AMP, fructose-2,6-BP
Allosteric regulation of pyruvate kinase
inhibited by ATP
activated by fructose-1,6,-BP
Hormonal regulation - induction by insulin of
glucokinase, PFK-1 and pyruvate kinase
Hormonal regulation - repression by glucagon of
glucokinase, PFK-1 and pyruvate kinase
Lactic acidosis
Results from a buildup of lactate in the cytoplasm caused by anaerobic glycolysis;
Caused by strenuous exercise
Alcohol intoxication causes
impaired gluconeogenesis
Leukemia/metastatic carcinoma
anaerobic glycolysis by tumor cells
How does pyruvate kinase deficiency result in hemolytic anemia?
Decreased ATP = impaired membrane of RBC –> cane the shape of cells –> cell lysis
Fructose
Glyceraldehyde-3-phosphate is the glycolitic intermediate and substrate for gluconeogenesis;
It can go into glycolysis or gluconeogenesis
Galactose
Glucose-6-phosphate is the glycolytic intermediate and the intermediate in gluconeogenesis;
Can proceed to glycolysis if the body is in the fed state or to glucose
Fructokinase deficiency
inability to metabolize fructose; causes build up of fructose in blood (benign and asymptomatic); build up excreted in urine
Hereditary fructose intolerance
aldolase B deficiency; vomiting, hypoglycemia, hepatomegaly; causes liver failure and death
Non-classical galactosemia
galactokinase deficiency; build up of galactose in blood and urine; leads to cataracts
Classical galactosemia
GALT deficiency; buildup of galactose-1-P; liver damage and mental retardation
What are the two main products of HMP and which pathways utilize them?
NADPH and ribose-5-phosphate;
NADPH is used for FA synthesis, cholesterol and steroids;
Ribose is used for nucleotide synthesis
Where is HMP active?
ovaries, testes, mammary gland, adrenal cortex, adipose tissue and liver
What is the role of NADPH in RBCs?
partcipates in the reactions for the formations of reduced glutathione from oxidized glutathione by glutathione reductase
What is the role of glutathione in RBCs?
needed for detoxification of hydrogen peroxide which is important in RBCs because it stabilizes the plasma membrane to maintain hemoglobin in the a reduced state
Inherited deficiency of G6PD
reduces the amount of NADPH produced in RBCs by making them more susceptible to hemolysis
Wernicke-Korsakoff encephalopathy
due to decrease in thiamine
sx: ataxia, confusion, eye paralysis, learning and memory deficits
How is PDH activity regulated?
AcetylCoA and NADH inhibit PDH through feed-back inhibition;
Activated by Ca++
Inhibited by ADP and pyruvate
The TCA cycle provides
CO2 and GTP for the ETC
What are the 2 types of anaplerotic reactions
- 4 and 5 carbon acids replenished via amino acid degradation
- Oxaloacetate regenerated from pyruvate by pyruvate carboxylase
What does the chemiosmotic hypothesis do?
couples the ETC to ATP synthesis
Uncouplers of ETC
DNP, UCP1, ASA;
Uncouple electron flow from ATP synthesis
Inhibitors of ETC
Block electron flow at different positions on the ETC
Free radicals
molecules with highly reactive unpaired electrons that can exist independently
Antioxidant defense enzymes
Catalase, superoxide dismutase, GSH, glutathione peroxidase
Antioxidant vitamins
Vitamin C, Vitamin E, Beta-carotene
Metal sequestration
Transition metal
What is the role of glycogenesis in the homeostasis of blood glucose levels?
Helps prevent hyperglycemia by sequestering blood glucose
Insulin stimulates glycogenesis by:
Increasing glucose transport into muscles cells by GLUT4;
Increasing glucose transport into liver by GLUT2;
Inhibits glycogenolysis
Glyocgen synthase
UDP-glucose attaches to non-reducing ends of glycogen
Branching enzyme
removes 6-8 gluce segment from non-reducing end
transfers this segment to an internal position
Insulin turns these things on
Glycogen synthase and Glycogenesis
Glucagon turns these things off
Glycogen synthase and Glycogenesis
Phosphorylase
breaks alpha 1-4 via phospholytic cleavage using Pi to produce G1Pq
Debranching enzyme
transfers 3 glucose residues from the end to the no-reducing end of the glycogen chain
Glucagon turns these things on
glycogen phosphorylase and glycogenolysis
Insulin turns these things off
glycogen phosphorylase and glycogenolysis
Type I
Glucose-6-phosphate
Type II
a-1,4-glucosidase
Type III
debranching enzyme
Type IV
branchign enzyme
Type V
glycogen phosphorylase
Type VII
phosphofructokinase
Type VIII
phosphorylase kinase
Bypass I of gluconeogenesis
Pyruvate –> oxaloacetate by pyruvate carboxylase
Bypass II of gluconeogenesis
Fructose-1,6-B,P –> fructose-6-P by F-1,6-BPase
Bypass III of gluconeogenesis
Glucose-6P –> glucose by gluco-6-phosphatase
How is the energy required for gluconeogenesis supplied?
FAs and glycerol from lipolysis
ATP and NADH from FA oxidation
What is on/off at low energy charge?
Gluconeogenesis is OFF
Glycolysis is ON
What is on/off at high energy charge?
Glycolysis is OFF
Gluconeogenesis is ON
DM Type 1
Lack of insulin results in repression of PEPCK –> gluconeogenesis is stimulated and glucose is produced –> hyperglycemia
Loss of pancreatic B cells
Insulin in liver activates/inhibits:
Activates: FA synth, glycolysis, glycogenesis, protein synth, HMP
Inhibits: gluconeogenesis, glycogenolysis
Insulin in adipose activates/inhibits:
Activates: TAG storage, glycolysis, HMP
Inhibits: lipolysis
Insulin in muscle activates/inhibits:
Activates: protein synth, glycogenesis, glycolysis
Glucagon in liver activates/inhibits:
Activates: glycogenolysis, gluconeogenesis, beta-oxidation, ketogenesis
Inhibits: glycolysis, glycogenesis, FA synth
Glucagon in adipose activates/inhibits:
Activates: beta-oxidation, lipolysis
Glucagon in muscle activates/inhibits:
Activates: protein degradation, beta-oxidation, ketolysis
Catecholamines in liver and muscle:
Activates glycogenolysis
Inhibits glycogenesis
Catecholamines in adipose:
Activates lipolysis
DM Type II
Non-insulin dependent diabetes
Insulin resistance combined w/inadequate insuline secretion
FISH
used to visualize labeled probes using fluorescence microscope
Chromosome painting
mixture of proves for a given chromosome
M-FISH or SKY
allows for simultaneous visualization of al chromosomes
Array CGH
compare pt DNA to control to determine abnormalities
Ploidy
change in chromosome number due to non-disjunction of sister chromatids during meiosis 1 or 2
Aneuploidy
gain of loss of individual chromosomes (gain is viable, loss if not)
ex: trisomy 13, 18, 21
Polyploidy
gain of entire chromosome set (not viable ever)
Downs syndrome
Trisomy 21; mental retardation, small stature, respiratory infections, characteristic facial appearance
Patau syndrome
Trisomy 13; congenital heart defects, seizures, hypotonia, cleft lip and palate, polydactyly
Edwards syndrome
Trisomy 18; low set and malformed ears, rocker bottom feet, clenched fist
Turner syndrome
45, X or 45XO; viable but not fertile; short, no secondary sex characteristics, mild mental retardation
Klinefelter syndrome
47, XXY most common; viable but not fertile; hypogonadism, elongated limbs
Reciprocal translocation
complete exchange of fragments between two broken non homologous chromosomes
Robertsonian translocation
translocation involving two acrocentric chromosomes; ex: Down’s syndrome!
Allele
different version of a gene in a population
Allele frequency
frequency of allele in population
Genotype
genetic makeup of a cell
Genotype frequency
proportion of individuals with a specific genotype
Autosomal dominant
every generation affected; males and females equally
Autosomal recessive
unaffected parents can have affected or unaffected kids; males and females equally
X-linked dominant
every generation affected; affected father only transmits to daughters; males and females equally
X-linked recessive
males more than females; unaffected males do not transmit; carrier women transmit to sons
Penetrance
the % of individuals w/the same genotype who express that phenotype
Expressivity
range of phenotypes produced by the same genotype
Locus heterogeneity
mutations in different loci that produce the same phenotype/disorder
Allelic heterogeneity
different mutations in the same locus that produce phenotypes of differing severity
Anticipation
progressively earlier age of onset and increased severity of sx (correlates w/increased number of trinucleotide repeats)
Multifactorial inheritance
disease process that has influence stemming from genetics and environmental interactions
Risk
disease susceptibility conferred by genes alone
Liability
factors affecting disease development
SNP
a DNA sequence variation occurring commonly w/n a population
Sanger DNA sequencing
for known and unknown mutations;
can identify SNPs/point mutations, deletions, insertions
Exome sequencing
for unknown mutations;
whole genome coverage
Microarray hybridization
for unknown and known mutations;
screen entire genome
Southern blotting
DNA;
for known mutations;
used for detection of relatively larger rearrangements on single gene;
used for trinucleotide repeat disorders
PCR amplification
for known mutations
RFLP analysis
for known mutations
ARMS PCR/allele-specific PCR
for known mutations
Biosynthetic pathway affected
the end product is usually important for cellular function and thus a decrease in levels is very detrimental
Catabolic pathway affected
a decrease in end product not as detrimental
Degradative pathways affected
accumulation of substrate is very detrimental
Screening
performed on healthy individual who might be at risk for developing disease
Diagnostic
performed on symptomatic individual to establish or confirm a diagnosis
Types of tx for metabolic disorders:
- Avoidance
- Enhancement (of residual enzyme activity)
- Protein replacement
Phenylketonuria (PKU)
Defect in phenylalanine metabolism –> elevated serum phenylalanine levels;
Sx: mental retardation, seizures, autistic behavior
Tx: dietary restriction
Hyperphenylalanemia
Defect in biosynth of cofactor required for phenylalanine hydroxyls activity;
Sx: muscle rigidity, dystonic movements, myoclonic seizures, drooling, microcephaly
Tx: not responsive to phe-free diet; supplement w/L-dopa and 5-OH tryptophan to restore neurotransmitter balance
Extensive metabolizers
normal activity and normal metabolism
Intermediate metabolizers
slightly reduced activity and slightly slower than normal metabolism
Poor metabolizers
low/no activity and almost no metabolism
Ultra-rapid metabolizers
higher than normal activity and faster than normal metabolism
Oncotype DX breast cancer assay
gene expression profile of 21 gene panel used to calculate recurrence score w/n 10 yrs of initial diagnosis and assess whether women will benefit from certain types of chemo
Mammaprint breast cancer assay
gene expression profile of 70 gene panel used to predict risk of metastasis over 10 years
Prevenio lung RS test
gene expression profile of 14 genes associated w/known molecular pathways in non-small-cell lung cancer
