hbio 420 midterm 1 important processes and other things

protein catabolism

amino acids are degraded via trans or deamination and carbon atoms are fed into the TCA cycle at various steps

glycolysis

occurs in cytoplasm and converts glucose to lactate or pyruvate to provide high power output (2 x that of glucose oxidation) without requiring o2

important enzymes include PFK (phosphofructokinase), pgk (phosphoglycerate kinase), and pyruvate kinase and glycogen phosphhorylase

pyruvate kinase activity 

depends on type: 

high in fg (type IIb/IIx where nrg is most concentrated

intermediate in FOG (Type IIa) 

low in SO (type 1) 

pyruvate post glycolysis 

anaerobic alcoholic fermentation (reduced to ethanol via ADH to regenerate NAD+) 

anaerobic homolactic fermentation (when pyruvate is produced faster than it can be oxidized through CAC at 75% VO2) 

NAD+ is remade through LDH 

pyruvate dehydrogenase

converts pyruvate to acetyl coa

PDH-P - inactive form which is inhibited by pyruvate, NAD+, CoA-SH and activated by NADH and acetyl coA

PDH - active form converted to PDH-P via PDH Phosphatase which is activated by Ca2+, Mg2+, AMP, ADP, and pyruvate and inhibited by ATP, NADH, and acetyl coA

CAC

located in matrix, convertgs acetyl coa into electron carriers

important enzymes citrate synthase, isocitrate dehydrogenase, alpha ketoglutarate dehydrogenase

yields 3 NADH, 1FADH2, 1 GTP per cyle

6 NADH, 2 FADH2, 2 GTP per glucose

citrate synthase

inhibited by ATP, NADH, succinyl coA

isocitrate dehydrogenase 

inhibited by ATP

activated by ADP and NAD+ 

alpha ektoglutarate dehydrogenase

inhibited by NADH and succinyl coa

activated by AMP

ETC

located in the inner mitochondrial memb rane with starting materials NADH and FADH2 and creates H2O and ATP

complex 1 (NADH-coenzyme Q reductase) pumps 4 protons

complex II (succinate coenzyme Q reductase) pumps 0 protons

complex III (cytochrome C reductase) pumps 4 protons

complex IV (cytochrome C oxidase) pumps 2 protons

complex V (ATP synthase)

oxidative phosphorylation via atp synthase 

3 protons move thorugh ATP synthase complex, rotating f0 and the gamma stalk —> 3 protons are exhanged for 1 

ways membrane otential is dampened uring atp synthase

ATP/ADP translocase and H+/pi symporter

ATP/ADP translocase

atp has one more negative charge than adp and moves out, dampening membraen

inorganic phosphate/H+ symporter

proton further dampens because it moves into the matrix 

malate aspartate shuttle

as nadh from glycolysis moves in, it is first converted to oxaloacetate and then is transported across inner mitochondrial membrane. once ni matrix, it is converted back to malate and NADH is created

slower but more efficient

g3p shuttle

nadh is oxidized and then donates electrons to FAD in complex 3 to make FADH2

faster but less efficient and used in brain, skeletal muscle, and insect flight muscles

where is lactate used 

heart and brain : for nrg 

liver and kidney: for gluconeogenesis

beta oxidation of fats

1) mobilization: triglyceride hydrolysis liberates fatty acids from triglycerides (these are stored in adipose tissue and it occurs through different enzymes depending on location

2) transport: hydrophobic lipids travel through blood in lipoproteins or bound to albumin

3) uptake: uptake through diffusion or CD36, FATP1, FATP4

• some diffuse through, but membrane bound cd36 and fabppm can accept fa from albumin

• cd36 cam tranpsort fas across membrane to cabpc

• fatp1 transports long chains of fatty acids

4) activation: fatty acyl synthase (ACS1) binds fatty acids to coA and activates it, making acyl coA —> this requires 2 ATP

5) translocation: across mitochondrial membrane via carnitine shuttle

6) oxidation: conversion to co2, h2o, atp via beta oxidation, tca cycle, and etc

diff types of triglyceride hydrolysis enzymes

lipoprotein lipase: blood

pancreatic lipase: in small intestine

adipose triglyceride lipase, hormone sensitive lipase, and monoacylgylycerol lipase in adipocytes and skeletal muscles 

carnitine palmitoyltransferase shuttle-

CPTI AND CPTII catalyze trasnfer of fatty acyl to make carnitine, regulating transport of fatty acyl across outer and inner mitochondrial membrane into matrix

CPTI takes acyl coA and adds carnitine to it making, acyl-carnitine and then transports this across outer membrane to IMS —> then transported into matrix via translocase (

• CPI available on outer membrane

CPTII converts acyl-carnitine back into carnitine and acyl-coA—> acylCoa is ready to be oxidized

• CPTII is available on inner membrane and converts acylcoa into carnitine to allow for transpot of carnitine back out of mitochondria

highly regulated and potentially rate limiting in FA

exercise and epinephrine regulating CPT 

exercise/epinephrine leads to inc in AMP and activates AMPK thorugh phosphoryoaltion. AMPK activates phosphorylation of ACC (acetyl coa carboxylase) which is inactivated. this prevents ACC (p) from converting acetylcoA to malonyl coA which is a negative regulator of beta oxidation because it is an intermediate in the synthesis of long chain FAs —> because malonyl coa is an intermediate in synthesis of long chain fas, decreased malonyl coa concentrations activate teh CPT enzyme and inc rate of fa entry into mitochondria 

random walk equation

• (∆Y)² = qi(Dt) (random walk equation)

  • Qi is a constant that depends on dimensionality (assume qi = 6 b/c everything in 3D)

  • D is diffusion coefficient

  • r  is distance traveled (m) in some time t(s)

stokes einstein equation 

• D = kT/f (Stokes-Einstein equation)

• Increased viscosity = increased radius of carrier molecule = decreased diffusion rate 

• K is a constant, T is temperature, f is frictional coefficient (6ˆπnr) 

  • n is the dynamic viscosity (resistance to flow) of the solution and r is the molecular radius

rate of diffusion of a substance across plasma membraen is proportional to what 3 factors

• membrane surface area

• concentration gradient across membrane

  • membrane permeability

where are aquaporins not expressed

• distal convoluted tubules and collecting ducts unless adh is expressed

• no aquaporins in ascending limb of loop of henle

osmolarity v molarity 

• osmlarity measures moles of solute particles rather than moles of solute 

• Body fluids have an average Osm of 290 (not 300 as stated by Silverthorn)

  • Includes the sum of all of each solutes

when should you provide lactated rigners or ringers or normal saline

ecf loss (hemmorhaging)

lactated ringer can also be provided as a buffer ot effects of acidosisd

what to give someone who is dehydrated

d5w (hypotonic), or normal saline and dextrose

what are colloids used for 

• high molecular weight solutions that draw fluids into intravascular compartment via oncotic pressure (exerted by plasma proteins) 

• examples include albumin, hetastarch, pentastarch, dextran 

• used for fluid resuscitation because they are good plasma expanders (hypertonic) 

channel proteins v carrier proteins

channel proteins are less specific but can be open or close, carrier proteins are always open with high specifity and can include uniport/symport/antiport

Na+/K+ ATPase pump how does it work

primary active antiport carrier protein

• 3 sodium ions from ICF bind to high affinity sites resulting in ATP to phosphorylate the carrier protein

• protein changes conformation and opens towards the ECF

• Na binding sites lose their affinity and release the 3 sodium ions into the ECF

• 2 potassium from ECF bind to high affiniyt sites on carrier proteins, releasing phosphate group bound to carrier protein

• potassium binding sites lose affinity and release 2 k+ into icf

• enzyme resets

types of endocytosis

• phagocytosis

• pinocytosis (cell drinking) 

• receptor mediated

• caveolae (lipid rafts —> not clathrin) 

• dynamin, a GTPase helps pinching off for endocytosis 

do skeletal muscles need mroe or less cholesterol

more

peptides

• water solubel and stored in secretory vesicles

• largest class

• include

  • peptide hormones: TRH, ANP, insulin, vasopressin

  • polypeptide/protein hormones: larger than peptide hormones and include hGH, oxytoxin

  • glycoproteins: protein + carb and include FSH, LH, TSH

peptide hormones storage and synthesis

• stored in secretory vesicles and dissolve in plasma —> used to activate 2ndary messengers like cAMP and modify proteins/alter protein synthesis

• synthesized as preprohormone, which has a signal sequence made of mRNA which leads it to the lumen of the rough ER

• signal sequence is then cleaved to form an inactive prohormone

• prohormone (proteolytic prohormone convertases) is then packaged by the golgi and then placed in vesicles with enzyes that make one or more active peptides and additional peptide fragments

• can reach circulation via calciumd ependent exocytosis 

• once they reach target cells, they bind receptors and activate signal transduction pathway typ through adenylyl cyclase to modify existing proteins (rapid) or affect synthesis of new proteins (slow) 

• then they are rapidly degraded via peptidases or excreted 

steroids 

lipid soluble class 1 enzymes 

• cholesterol derived lipophilic hormones that can easily cross membranes 

• made prn in smooth er and not stored in vesicles (lipophilic) 

• primarily acts on nuclear cell receptors, but may have some membrane/cytoplasmic receptors and targets (esp endothelial cells) 

• slower acting due to genomic effects 

s

steroid hromone synthesis and transport

• cholesterol is converted to pregnenolone (key 3 ring intermediate 1conjugated 5 carbon ring) which is then converted to progesterone

• primarily synthesized by adrenal cortex, gonads (testes, ovaries, placenta)

• extra glandular and peripheral steroidogenic tissues include

  • brain (glial cells for neurosteroids), skin (epidermis and sebaceous glands), adipose tissue, immune cells (macrophages and t lymphocytes), heart, thymic epithelial cells, and intestinal mucosa

classes. of steroid hormones

• estrogen

  • estrone (menopause)

  • extradiol (normal)

  • estriol (pregnant)

progestagens

different zones of adrenal gland cortex that produces these different steroids 

• glomerulosa: mineralocorticoids like aldosterone

• fasciculata: glucocorticoids like cortisol

• reticulus is androgens 

steroid transport

steroids bind carrier proteins in blood due to lipophilicity resulting in a longer half life 

• once bound to carrier proteins, they are considered inactive 

  • CPs can be specific or nonspecific and may or may not dissociate hormones at target tissues due to how tightly bound they are to steroids

• steroid hormoenes thenbind to receptors in target cell cytoplasm/nucleus

• class I receptors dimerize then binds to HRE (hormone response element) sections in DNA and affects gene transcription through slow response

• steroid hormoens then inactivatedin liver

amine hormones 

1) catecholamines

2) indoleamines

3) thyroid hormones 

catecholamines

• water soluble (NED) made from tyrosine

• produced by adrenal suprarenal medulla and includes epi, norepi, dopamine

• stored in secretory vesicles and released via exocytosis —> then dissolved in plasma and bind to receptors on target cell memrbaens to activate secondary messenger systems and modify existing proteins

• short half life

indoleamines

• melatonin and serotonin made from tryptophan

• amphiphilic

thyroid hormones 

• lipid soluble and include t3/t4 made from tyrosine 

synthesis

• 1) thyroglobulin is synthesized in smooth er and then exported ot thyroid follicular lumen 

• 2) iodine added to thyroglobulin (Tg) to make a colloid 

  • *hydrogen peroxide is required to add iodine to thyroglobulin, which occurs outside of cell due to toxicity

  • glutathione peroxidases are upregulated during thyroid hormone syntehsis to mitigate the effects of h2o2

• 3) TSH binds to cell receptors, triggering uptake of Tg colloid back into cell

• 4) Tg is then proteolytically cleaved to produce T3 and T4 which bind to thyroxine binding protein (TBP) and some to albumin (t4 also binds transthyretin)

• 5) t3 and t4 travel to target cells where t4 is activated to t3 via dio1-3 (diodinases1-3)

  • some t3 is also converted to rT3 and T2 for negative feedback

  • t3 enters cells through monocarboxylate transporter 8 and 10 and organic anion rtransporting polypeptide 1c1

• 6) T3 enters the nucleus and binds to thyroid receptors to activate gene expression via thyroid response elements (TREs) 

  • T3 can act nongenomically or genomically, but if it acts genomically, it has a longer half life

indoleamines

• from tryptophan

  • serotonin: water soluble

  • melatonin: amphipathic but mostly lipid soluble

how does melatonin work

• Ganglionic cells in retina detect absence of day light

• relayed info to suprachiasmatic nuclei

• norepinephrine activates protein kinase A (PKA)

• PKA phosphorylates AANT (biosynthetic enzyme)

• active AANT is penultimate enzyme in melatonin production in pineal gland (so activates melatonin production)

• melatonin is amphiphillic and †herefore transported by albujin in the blood

• melatonin binds to GPCRs (MT1/2) in target tissues that can be neuronal (sleep/wake) or non-neuronal (libido, maturity, puberty) 

• melatonin is permission to sleep and not sleep pressure; this is adenosine (built up from being freed from atp thorughout the day) 

plasma membrane breakdown by weight percentages 

42% phospholipid

55% membrane proteins

3% membrane carbs (glycocalyx coat is a sticky coat that forms outside cell membrane

blood products 

whole blood: signifcant blood loss (not really used anymore unless in war) 

packed rbcs: anemia

FFP: clotting factor deficiencies

cryoprecipitate: fibrinogen deficiencies

platelets: thrombocytopenia or bleeding disorders 

parathyroid cells and blood caclium

• low plasma calcium levels alert parathyroid cells —> results in the release of parathyroid hormoen to the bone and kidney —> once it notifies bone and kindey, there is increased bone resorption (breakdown), increased kidney reabsorption of calcium, and increased production of calcitriol which increases intestinal absorption of calcium —> calcium levels are increased, which is then negative feedback on parathyroid cell

• the kidney also produces calcitriol and the thyroid produces the opposing calcitonin

tropic, trophic, nontropic, tropin

• tropic: affect growth, function, nutrition of other endocrine cells including anterior pituitary hormones

  • TSH, ACTH, LH/FSH

  • *none of hte hypothalamic hormones are trophic

• tropic: affect other endocrine glands as their target to release hormones

  • all hypothalamic hormones that affect anterior pituitary

  • anterior pituitary hormones that affect thyroid, adrenal cortex, gonads

• tropin: suffix that typically refers to tropic hormones

hypothalamus produces 

• releasing hormones

• somatostatin

• vasopressin (ADH) and oxytosin

• dopamine and neurotensin 

anterior ituitary (Adenohyphophysis) produces

• TSH, ACTH, LH, FSH

• Prolactin

• growth hormone (somatotropin)

class v class ii nuclear receptors

• class I - location before ligand binding is in cytoplasm and ligand type is steroid hromoen (cortisol, estrogen, testosterone, aldosterone)

  • ligand binds to cytoplasm receptor, which releases heat shock and chaperone proteins which translocates into the nucleus and the class 1 receptors dimerize and binds to the HREs whic is a reigon on the promoter of the genes 

• class ii - location before ligand binding is in the nucleus and ligand type is non-steroid hormones like thyroid hormones, vitamin d, retinoic acid

  • after the hormone binds to nuclear receptors in the nucleus, release of a corepressor from the complex is triggered, allowing complezx to go turn on gene transcription on dna

thyroid hormone cascade

1) hypothalamus releases TRH stimulating anterior pituitary to produce TSH

2) TSH is secreted to thyroid gland and stimulates growth of thyroid cells and sythesis/secretion of thyroid hormones T3 and T4

3) T3 and T4 feed back to hypothalamus to decrease TRH and decrease TSH from anterior pituitary —> long loop 

waht does the thyroid do

• adults: inc, oxygen consumption, inc thermogenesis, affects protein/carb/fat metabolism

• children: necessary for normal growth and development, esp in nervous system synapses, myelin, and bone —> needed for full expression of growth hormone

hypothyroidism in adults

• often due to HASHIMOTOS thyroiditis disease (autoimmune, iodine deficiency, pituitary tumor

• symptoms include:

  • dec. metabolic rate

  • dec. thermogenesis (cold intolerance)

  • dec protein synthesis (brittle nails, thin hair, thin skin)

  • effects on nervous system include fatigue, slow reflexes, slow speech and thought

hypothyroidism in infants 

• cretinism 

• due to congenital defect or absence of thyroid gland 

• impaired physical growth and maturation 

• mental retardation

• infertility 

other general symptoms of hypothyroidism

• myxedema: swelling of soft tissue

• goiter: enlargment of thyroid gland (bc thyroid strains itself to makeup for thyroid hormone deficit by relesaing TSH, can be a result of hypothyroidism)

hyperthyroidism in adults

• due to GRAVES disease (autoimmune) which produces thyroid stimulating immunoglobulins (TSI) that mimic action of TSH

• can also. be due to thyroid or pituitary tumors or htyroiditis

• symptoms:

  • inc metabolic rate

  • inc thermogenesis (heat intolerance)

  • inc protein catabolism (muscle weakness and weight loss)

  • inc beta 1 adrenergic receptors in heart (positive chronotropic and inotropic effects)

  • exophthalmos (bulging eyes)

—> can be primary, secondary, or tertiary

HPA axis/cortisol hormone cascade 

1) corticotropin releasing hormone (CRH) stimualtes anterior pituitary to produce adrenocorticotropic hormoen aka corticotropiin

• ACTH can feedback in a shor tloop to inhibit the hypothalamus from releasing CRH

2) adrenocorticotropic hormoen (ACTH) stiulates growth of adrenal cortex (trophic hormone) and stimulates synthesis and secretion of glucocorticoids 

3) glucocorticoids (ie. cortisol) feed back to hypothalamus to decrease levels of CRH and to anterior pituitary to decrease levels of acth 

4) cortisol targets all nculeated cells to influecne metabolism, stress, response, etc 

what organs in adrenal gland produce waht

• inner medulla produces catecholamines

• outer cortex produces steroid hormones 

glucocorticoids

• class 1 receptors

• essential for preventing hypoglycemia and has a permissive effect on glucagon and catecholamine (due to activation glycogen phosphorylase)

• critical for responding to stress

• excessive use results in brittle bones (negative calcium balance)

  • suppresses immune system

hypercortisolism

• CUSHING syndrome, via adrenal cortex tumor that secretes cortisol or pituitary tumor that autonomously secretes ACTH

• symptoms

  • inc gluconeogenesis (hyperglycemia/diabetes)

  • inc muscle protein breakdown (muscle weakness)

  • inc catabolism (tissue wasting, thin skin, easy bruising)

  • inc appetite (moon face, buffalo hump, abdominal obesity)

  • inc bone breakdown

  • dec inflammation

  • effects on brain include depression, cognitive impariments

  • DEC GnRH

• can result in iatrogenic hypercortisolism (dependeny on prescription drugs) 

hypocortisolism 

• ADDISONS disease (uncommon) 

• hyposecretory disorder of adrenal cortex

• deficiencies in both mineralocorticoids and glucocorticoids (typ due to autoimmune destruction of adrenal cortex) 

short loop feedback

• prolactin

• GH

• ACTH

• GAP

• feedback of pituitary hormone to hypothalamus

exceptions to hypothalamic hormones for long loop feedback

• ovarian estrogen and progesterone (switch to positive feedback loops)

prolactin release 

• prolactin is secreted from anterior pituitary in response to eating, mating, estrogen treatment, ovulation, nursing and stimulates milk synthesis in breasts 

• other effects include fertility, immune function, maternal/paternal behavior

pathway: sound of child crying stimulates hypothalamus to decrease PIH (prolactin inhibiting hormone) which removes inhibition on prolactin cells and allows for increased prolactin to go to breasts and stimulate milk secretion

• prolactin is involved in short loop feedback because it can go back to the hypothalamus and activate the PIH cells

growth hormone axis 

• peak GH released during the teenage years

• growth hormone releasing hormone (GHRH) can go to anterior pituitary and stimulate release iof growth hormone

• excess growth hormone can be turned into somatostatin which can inhibit the production of GHRH (antagonistic to GHRH) —> short loop

• growth hormoen then goes to liver and other tissues to stimulate the secretion of insulin like growth factors (IGF-1, IGF-2), which function as major mediators of growth hormone stimulated somatic growth via TRK receptors and GH independent anabolic responses in many cells and tissues 

  • IGFs can do long loop feedback on hypothalamus and pituitary

• stimulates bone, cartilage, muscles, and other soft tissue growth 

• increases fat breakdown —> inc fatty acids in blood

• inc glucose release from liver —> inc plasma glucose levels

• promotes protein synthesis 

*GROWTH HORMONE IS ALSO CALLED SOMATOTROPIN

abnormalities of growth hormone 

• GH deficiency in childhood - dwarfism 

• GH excess in childhood - gigantism 

• GH excess in adulthood - acromegaly 

pancreas and major hormone products

• islet of langerhands have 4 cell types that produce diff peptide hormones including

  • beta cells (insulin)

  • alpha cells (glucagon)

  • d cells (somatostatin)

  • p (f) cells (pancreatic polypeptide

example of permissiveness

• presence of one hormone is required in order for other hormoen to exert its full potential 

• GnRH, FSH AND LH, and gonadol steroid hormones and T3 are all required for maturation —> t3 is permissive to development 

how does pyruvate enter mitochondria

enters outer membrane through porin 

enter sinner membrane through mitochondrial pyruvate carreier (MPC)

pyruvate kinase regulators

• stimulated by ADP

• inhibited by ATP 

four types of enzymatic reactions

1) redox

2) hydrooysis-dehydration

3) transfer chemical groups

4) ligation w

what happens at 75% VO2 max

• lactate production exceeds disposal rate in muscle, hence exported with proton via MCT-1

what is putative mechanism for mitohcondrial oxidation of lactate (mloc) 

lactate is produced in cytosol and oxidized in mitochondria by mLDH which is attached to cyt c oxidase —> it is converted ot pyruvate and NADH 

what does AMP activate 

glycogen phosphorylase and PFK (glycolysis) 

phosphofructokinase regulators 

• stimulated by AMP, ADP, Pi, NH4+ 

• inhibited by ATP, PCr, citrate

located in type 2x skeletal muscle fibers and low in type 1, 2a

what rxn occur in phosphagen system

CrP phosphyorylating ADP via creatine kinase

ADP autophosphorylating via adenylate kinase

amp and acidosis connection

• AMP + H+ —> IMP + NH4+ (takes up one proton) via AMP deaminase

• metabolic acidosis activates AMP deaminase

PGK regulators 

• fructose 1 6 bisphosphate

• AMP activates

• ADP activatres

• ATP inhibits 

glycogen phosphrylase regulation

• turns glycogen to glucose

• activated by AMP, Pi, Ca2+

pyruvate dehydrogenase complex

1) pyruvate dehydrogenase catalyzes first 2 rxns

2) dihydrolipoyll transacetylase catalyzes next rxn (acetyl coA made here)

3) dihydrolipoyl dehydrogenase catalyzes next two rxns (NADH made here)

4 major CK isozymes

1) MM-CK (m line of skeletal muscle)

2) BB-CK (brain, smooth muscle, NS) 

30 miu ck (mitochondrial) 

4) mis-ck (mitochondrial octomer, creatine phosphate shuttle, phosphate from itochondria to myofibrils_

thymosin and thymopoietin effects

lymphoscyte development

these are secretred by thymus gland

what hormones are secreted by stomach and small intestine and what are their targets???

plasma makckeup

• Plasma is made of Na+, glucose, BUN, and EtOH

why can we estimate ecf/icf

bc the connective tissue water doznt diffuse easily and is 15%

• Interstitial fluid: Na+, Cl-

• ISF is formed when plasma filters out of the capillaries into the spaces between cells

• Most of the filtered fluid is reabsorbed at the venous end of capillaries