What type of metabolic regulation is most rapid? Which is the longest lasting?&nbsp;Rapid: allosteric, feeback, and phosphorylation<div>Gene expression: longest lasting</div><div><br></div><div>Medium-length: hormonal</div>
What physiological changes can alter hormone secretion?&nbsp;tumors, infection, damage to an endocrine gland, genetic disorders, problems with the feedback system, aging, food intake/depleted stores of vitamins/minerals
paleolithic era / agricultural era / modern era (time range, type of activities, and general health and diet)paleolithic era:&nbsp;<div>- 2 million to 10,000 years ago</div><div>- hunter/gatherer</div><div>- short lifespan, focus on adequate intake</div><div><br><div>agricultural era:&nbsp;</div><div>- 10,000 to 2,000 years ago</div><div>- farmers/pastoralists</div><div>- short lifespan, focus on adequate intake; dental decay, iron deficiency, decreased height, delayed puberty</div><div><br></div><div>modern era:&nbsp;</div><div>- last 50 years</div></div><div>- industry/service jobs</div><div>- increased liefspan, obesity, diabetes, atherosclerosis, and 6 inches taller!! earlier puberty</div>
Neandertal bone discoveryneandertal bone collagen showed they ate mainly meat, but also had carbs as an important part of their diet <i>BUT</i> in the form of tubers, nutes, and honey
Ideal american dietary habits (protein, fat, carbs, fiber, veg, fruit, dairy, meat, fat)protein: 12-14%<div>fat: 30%</div><div>carbs: 60%</div><div>fiber: 10%</div><div>veg: 3 cups</div><div>fruit: 1.6 cups</div><div>dairy: 2-3 cups</div><div>meat: 5 oz</div><div>fat: 22 tsp</div>
dietary guideline highlights (salt, added sugars, fiber, calcium, and core foods)salt: <b>reduce </b>to &lt;2,300 mg/day<div>added sugars: reduce to &lt;10% daily intake</div><div>fiber: 25-30 g/day</div><div>calcium: increase in general for americans</div><div>core foods: veg, fruit, whole grains, low fat, lean and plant based, modest oils</div>
top 3 causes of death in US (2020)heart disease, cancer, and COVID <b>(all nutrition-related)</b><div><i>adtl: 8 is diabetes</i></div>
c8be5b0245374f45980272ce343db634-oa-1"<img src=""Screen Shot 2021-09-14 at 4.47.45 PM.png"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-1-Q.svg"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-1-A.svg"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-O.svg"" />"
c8be5b0245374f45980272ce343db634-oa-2"<img src=""Screen Shot 2021-09-14 at 4.47.45 PM.png"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-2-Q.svg"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-2-A.svg"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-O.svg"" />"
c8be5b0245374f45980272ce343db634-oa-3"<img src=""Screen Shot 2021-09-14 at 4.47.45 PM.png"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-3-Q.svg"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-3-A.svg"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-O.svg"" />"
c8be5b0245374f45980272ce343db634-oa-4"<img src=""Screen Shot 2021-09-14 at 4.47.45 PM.png"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-4-Q.svg"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-4-A.svg"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-O.svg"" />"
c8be5b0245374f45980272ce343db634-oa-5"<img src=""Screen Shot 2021-09-14 at 4.47.45 PM.png"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-5-Q.svg"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-5-A.svg"" />""<img src=""c8be5b0245374f45980272ce343db634-oa-O.svg"" />"
draw the monosaccharides"<div>hayworth projections // where one line = OH, two lines = carboxyl</div><img src=""Screen Shot 2021-09-14 at 5.08.31 PM.png"">"
draw the three common disaccharides. which are alpha and beta? which monosaccharides?"<div>lactose: only beta, others are alpha</div><div><img src=""Screen Shot 2021-09-14 at 5.10.10 PM.png""><br></div>"
are beta glycosidic bonds digestible?&nbsp;<b>no </b><i>except </i>lactose, which is Beta 1-4 gal-glu
draw the three common polysaccharides. what bonds? which monosaccharides?"<div>cellulose: beta and indigestable by gut microbiome</div><img src=""Screen Shot 2021-09-14 at 5.13.58 PM.png"">"
what complex polysaccharide(s) can be digested in the gut microbiome?amylopectin (plant food storage) and glycogen (animal food storage)
Can you eat animal extracellular matrix?yes, in bones in soup for ex
forms of carbs we consume (5)1. extracellular matrix (hyaluronoic acid, chondroitin sulfate)<div>2. plant cell wall &amp; matrix (digestible fibers like hemicellulose, trehalose from mushrooms, &amp; raffinose from legumes)</div><div>3. membrane glycoproteins (sialic acid, fucose, glucosamine)</div><div>4. DNA &amp; RNA (ribose &amp; reoxyribose)</div><div>5. additives that emulsify foods (carrageenan aka galactose sulfate, gums, pectins, etc.)</div>
order of intestines:&nbsp;DJ's IC<div>duodenum, jejunum, ileum, colon</div>
Overall, what type of reaction dominates in carb digestion?hydrolysis
order of carb digestion (includes enzymes, locations, and type of rxn, ex: hydration)mouth: salivary amylase (homogenization, hydration, and starch hydrolysis)<div>stomach: peristalsis</div><div>duodenum: trypsin and pancreatic amylase including maltase, lactase, and sucrase (further hydrolysis to monosaccharides)</div><div>jejunum/ileum: absorption</div><div>colon: fiber fermentation and absorption of microbial products</div>
what four bonds can intestinal enzymes cleave?1. alpha 1,4 glu-glu: amylose, amylopectin, isomaltose, maltose<div>2. alpha 1,6 glu-glu: amylopectin (starch branch)</div><div>3. alpha 1,2 glu-fru: sucrose</div><div>3. beta 1,4 gal-glu: lactose</div>
intestinal transport of glucose and galactose vs fructoseglucose &amp; galactose: active transport<div>fructose: facilitated transport</div>
lymph continuumthoracic duct --&gt; heart --&gt; rest of the body
why does transport in the enterocytes work?concentration gradient:&nbsp;<div>low concentration in the lumen --&gt; high concentration in the bloodstream</div>
brush border (surface area mechanism, feeding tube complication, luminal vs contralateral side)<div>increasing surface area:&nbsp;</div>- mucosal cells line the villi<div>- a single mucosal cell has a verogated border as well, the microvilli</div><div><br></div><div>complexity: gut atrophies when you are on feeding tubes bc not as much contact or need for the complex structure of the mucosal cells&nbsp;</div><div><br></div><div>luminal side: active transport to bring them in the mucosal cells. huge SA with hydrolytic enzyme rich (low to high)</div><div><br></div><div>contraluminal side: facilitative, few microvilli, and downhill gradient (high to low)</div>
hepatic portal system function- liver: control<div>- prevents organs from competing unfairly for nutrients (except small intestine)</div>
when does diffusion occur in a cell membrane?"<b>never!!! </b>that's what the cell membrane is for. diffusion&nbsp;<span style=""font-weight: bold;"">only </span>happens intracellularly (ie mitochondria, ER, etc)&nbsp;"
is pinocytosis or endocytosis concentration dependent?no, concentration independent
describe the graph of the rate of facilitated diffusion"<div>levels out at max speed, it can only go so fast when mediated.</div><div><br></div><img src=""Screen Shot 2021-09-14 at 5.56.51 PM.png"">"
GLUT transporters (name, type of transport, types and tissue specificity)<div>Name: GLUT/sodium-independent glucose transporter&nbsp;</div><div><br></div><div>Type of transport:<b> all facilitated diffusion </b>and can be bi-direcitonal, but usually is focused, <i>except </i>glut 2 which is in and out.</div><div><br></div><div>Types:&nbsp;</div><div>GLUT 1: RBC's, sole source of energy is glucose.&nbsp;</div><div>GLUT 2: liver, kidney, beta cells (insulin-prod)&nbsp;</div><div>GLUT 3: neurons/brain</div><div>GLUT 4: muscle and adipose tissue, <b>not </b>liver, which is impt in insulin signaling (insulin responsive!)</div><div>GLUT 5: small intestine and testes (primary fructose transporter!)</div>
fructose interesting signalling fact"<div>Fructose&nbsp;<span style=""font-weight: bold;"">doesn’t&nbsp;</span>signal insulin</div>"
SGLT-1 (name, location, transport mechanism, function)"<div>Name: sodium-dependent glucose transporter aka sodium-monosaccharide <b>cotransport </b>system</div><div><br></div><div>Location:&nbsp;in the intestine, renal tubules, and blood brain barrier</div><div><br></div><div>Transport mechanism: active transport (of galactose and glucose only -- not fructose) <b>very efficient </b>with <b>high kinetic rate </b>and <b><u>most responsible</u>&nbsp;</b>for elevated blood glucose after a meal. active transport from lumen to mucosal cell, facilitative transport (export) from cell to capillary.</div> <div><br></div> <div>Function: <span style=""font-weight: bold;"">Really important </span>to expend as much energy as is necessary for this – bc it’s absolutely imperative that the brain gets glucose, as well as that the renal tubules can keep glucose in as needed and we can absorb as much as possible.&nbsp;</div>"
SGLT1 net reaction and draw mechanism"<img src=""Screen Shot 2021-09-14 at 6.15.04 PM.png"">"
Tissues' preference for glucose<div>RBC: sole CHO source</div><div>Brain: primary, but also ketones okay</div><div>Skeletal muscle: prefers FAs</div><div>Exercising muscle: initially glucose, but later glycogen</div><div>Other tissues: flexible</div>
FIRST STEP IN USING GLUCOSE ANYWHEREphosphorylation (add PO4): traps glucose in the cell for further metabolism
kinase, phosphorylase, phosphatasekinase: adds PO4 from ATP<div>phosphorylase: adds PO4 from inorganic PO4</div><div>phosphatase: removes PO4</div>
&nbsp;enzyme naming mechanismsubstrate + action + -ase
how much energy does it cost to phosphorylate glucose?&nbsp;1.3 ATP
glucose phosphorylation (function, how, and types of mechanisms)"<div><div>Function: make glucose 6 phosphate.&nbsp;</div><div><br></div><div>How: <b>TWO </b>mechanisms, with two different fates:&nbsp;</div><div><u><span style=""font-weight: bold;""><br></span></u></div><div><span style=""font-weight: bold;"">1. Hexokinases I-III</span></div> <div>- Ubiquitous (aka non-specific), less efficient</div> <div>- <font color=""#f67fe7"">Inhibited by glucose 6 phosphate (product feedback)</font></div><div>- dominates before a meal</div><div>- Low Km, Low Vmax</div><div><br></div> <div></div> <div><span style=""font-weight: bold;"">2. Glucokinase (hexokinase IV)</span></div> <div>- Liver specific, <i>highly</i>&nbsp;efficient&nbsp;</div><div>- <font color=""#f67fe7"">inhibited by fructose 6 phosphate</font></div><div>- dominates after a meal, directs G6P to glycogen</div> <div>- High Km (specificity!), High Vmax</div></div>"
Glucose phosphorylation: draw enzyme activity vs glucose concentration w graph and draw glucose phosphorylation rxn"<img src=""Screen Shot 2021-09-14 at 7.11.18 PM.png""><div><img src=""Screen Shot 2021-09-14 at 7.11.29 PM.png""><br></div>"
MODYName: maturity onset diabetes (T2DM) of the young<div>Function: Inherited disorder which causes children to not be able to efficiently reduce blood glucose</div><div>How: When glucose or G6P is high, glucose kinase activates. When glucose drops, glucokinase regulatory protein (GKRP) inactivates it.&nbsp;</div>
Glucokinase regulation exampleMODY
first gene identified as having an association with T2DMglucokinase regulatory protein (GKRP); overactive
excess energy vs low energy<div>excess energy</div>- hormone: insulin<div>- primary enzymes <b>before </b>process: <b>glucokinase,</b> phosphoglucomutase, glucose 1-P, uridylyltransferase, glycogen synthase<br><div>- process: glycogenesis</div><div><br></div><div>low energy</div><div>- hormones: glucagon and epinephrine</div><div>- primary enzymes <b>before </b>process: <b>hexokinase</b>, phosphofructokinase</div><div>- process: glycolysis</div></div>
Glycolysis orderglucose / G6P / F6P / F16BP / Glyceraldehyde 3 P / 1,3 BPGlycerate / 3 phosphoglycerate / 2 phosphoglycerate / phosphoenolpyruvate / pyruvate
which steps of glycolysis are irreversible?F6P to F16BP<div>Phosphoenolpyruvate to pyruvate</div>
rate limiting steps of glycolysis<div>F6P to B16 via PFK (-1 ATP)<br></div><div>PEP to pyruvate (+2 ATP)</div>
2 phases to obtain energy from glucoseenergy investment phase:&nbsp;<div>first five reactions of glucose costs 2 ATP</div><div><br></div><div>energy generation phase:&nbsp;</div><div>yields 4 total ATP (2 from ATP via production of 4 and subtraction of 2 from energy investment phase, and 2 via NADH if aerobic)</div>
glycolysis: draw rxn"<img src=""glycolysis-mcat-revised.jpeg"">"
TCA cycle: draw reaction"<img src=""tca-cycle-mcat.jpeg"">"
How is PFK regulated?"<font color=""#f67fe7""><b>inhibited by ATP and citrate (TCA intermediate)</b></font><div><b>activated by AMP and fructose 26 biphosphate</b>&nbsp;</div><div><i>NOTE: F26BP only in white adipose tissue and liver. Mechanism: <b>PFK-2</b> is active when dephosphorylated, favoring the production of F26BP, which activates <b>PFK-1</b>, increasing the rate of glycolysis, specifically the conversion of <b>F6P to F16BP.&nbsp;</b></i></div>"
where is F26BP made? underwhat conditions? what enzyme?location:&nbsp;<b>only </b>in liver and adipose<div>conditions: under insulin</div><div>enzyme: PFK-1</div>
81a4bef98d4947549cd0342b3906f09c-ao-1"<img src=""Screen Shot 2021-09-14 at 10.14.17 PM.png"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-1-Q.svg"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-1-A.svg"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-O.svg"" />"
81a4bef98d4947549cd0342b3906f09c-ao-2"<img src=""Screen Shot 2021-09-14 at 10.14.17 PM.png"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-2-Q.svg"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-2-A.svg"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-O.svg"" />"
81a4bef98d4947549cd0342b3906f09c-ao-3"<img src=""Screen Shot 2021-09-14 at 10.14.17 PM.png"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-3-Q.svg"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-3-A.svg"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-O.svg"" />"
81a4bef98d4947549cd0342b3906f09c-ao-4"<img src=""Screen Shot 2021-09-14 at 10.14.17 PM.png"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-4-Q.svg"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-4-A.svg"" />""<img src=""81a4bef98d4947549cd0342b3906f09c-ao-O.svg"" />"
where is pyruvate kinase phosphorylated<b>liver <u>only,</u>&nbsp;bc of making PEP for gluconeogenesis</b>
pyruvate kinase naming<div><b>not </b>fitting with the typical naming scheme of substrate + function + ase;&nbsp;</div><div>converts phosphoenolpyruvate into pyruvate, not the other way around!</div>
pyruvate kinase regulation and special function"<font color=""#f67fe7"">inhibition: ATP + protein kinase A --&gt;&nbsp; phosphorylation --&gt;&nbsp;<b>inactivates PK</b>, which makes it serve a <b>different function, </b>converting PEP to pyruvate for gluconeogenesis.&nbsp;</font><div><br></div><div>activation: F16BP, AMP and <b>creates glycolytic flux </b>to inactivation (by converting ADP to ATP in conversion of PEP to pyruvate, initiating inhibition).</div>"
anaerobic glycolysis (function, substrate &amp; product, enzyme, reversibility, common location)<div>Function:&nbsp;</div><div>- oxidizes carbonyl to make lactate using NADH</div><div>- important <i>especially </i>for poorly vascularized tissues, cells lacking mitochondria, and hypoxic tissues</div><div>- regenerates NAD for another round of glycolysis&nbsp;</div><div><br></div><div>reversible or irreversible: reversible</div><div>substrate: pyruvate</div><div>product: lactate</div><div>enzyme: lactate dehydrogenase</div><div><br></div><div>common location: skeletal muscle, requires elevated NADH/NAD+ ratio, favoring lactate production</div>
glycolytic net energy yield (aerobic vs anaerobic)<div>aerobic: 6 ATP (2 ATP and 2 NADH, aka 4 ATP from NADH)</div><div>anaerobic: 2 ATP (no net gain from NADH)</div>
LDHRegenerates NAD+ for generation of more energy via glycolysis&nbsp;
what two organs regenerate pyruvate from lactate for TCA?&nbsp;heart and liver
can every cell undergo the TCA cycles?&nbsp;"<b style=""""><u>not</u> </b>red blood cells"
pyruvate dehydrogenase (function, regulation, coenzymes, location, and products)<div>function: Pyruvate dehydrogenase links glycolysis and TCA cycle</div><div><br></div><div>regulation:</div><div>- energy status</div><div>- PDH kinase&nbsp;<br>- PDH phosphatase</div><div><br></div><div>5 coenzymes:&nbsp;</div><div>- thiamin decarboxylates pyruvate</div><div>- lipoic acid receives Ac from thiamin</div><div>- pantothenate/B5, CoA final recipient</div><div>- niacin, NAD+ catalytic in carboxylation</div><div>- riboflavin, FAD+ regenerates NAD</div><div><br></div><div>location: mitochondrial matrix</div>
pyruvate dehydrogenase: draw"<img src=""Screen Shot 2021-09-14 at 11.04.16 PM.png"">"
possible fates of pyruvate<b><u>glucagon:</u></b> oxidative decarboxylation of pyruvate to acetyl CoA&nbsp;<b>or </b>oxaloacetate to replenish TCA intermediates. Oxaloacetate can be used for gluconeogenesis, acetyl coa goes directly into TCA.<div><br></div><div><b><u>insulin:</u></b> oxidative decarboxylation of pyruvate to acetyl CoA for fatty acid synthesis</div><div><br></div><div><b><u>other:</u></b> amidation of pyruvate to make alanine for protein synthesis. also, ethanol and lactate.</div>
TCA cycle net energy generationeach turn (2 per glucose):&nbsp;<div>12 ATP total; 3 NADH (x3 = 9), 1 FADH2 (x2 = 2), 1 GTP (x1 = 1)&nbsp;</div>
TCA cycle regulation<div>1. pyruvate kinase</div><div>2. PDH</div>3. citrate synthase (inhibited by ATP, NADH, succ Coa, and LCFA)<div>4. isocitrate dehydrogenase (activated by ADP and <i>inhibited </i>by ATP and NADH)</div><div>5. alpha-ketoglutarate dehydrogenase (inhibited ATP, GTP, NADH, and succinyl-CoA)&nbsp;</div>
Total net ATP of cellular respirationglycolysis = 6 ATP<div>PDH = 6 ATP</div><div>TCA = 24 ATP</div><div><br></div><div><b>TOTAL = 36 ATP</b></div>
which tissues make glycogen?skeletal muscle (low density)<div>liver (high density)</div><div>white adipose tissue, kidney, heart (trace amounts)</div><div>placenta (late term/birth transition)</div>
glucose needs and how to compensate throughout the daydaily glucose requirement (adult) = 160 g; 100-140 is used by the brain<div><br></div><div>hepatic glycogen stores = 100 g, can provide glucose to peripheral tissues for 10-18 hours. dominant in between meals. (at night!)</div><div><br></div><div>gluconeogenesis meets excess need, activated 4-6 hours before a meal <i>mainly when glycogen is depleted</i></div>
glycogen density in muscle vs liver<div>liver = densist source of glycogen. has glucokinase for this reason. muscle lacks glucokinase so it can make it slower and not grow too quickly.&nbsp;&nbsp;</div>
glycogenolysis water requirements<div>- Must drink water bc&nbsp;water is required for breakdown of complex&nbsp;brancing&nbsp;(hydrolysis)<br></div><div>- Also&nbsp;the reason why you urinate in the morning,&nbsp;bc&nbsp;your main source of energy is glycogenolysis, which releases H2O (dehydrog/condensation)</div>
glycogen-relevant enzymes in different energy levelslow energy: G6P--&gt; F16P --&gt; glycolysis<div><br></div><div>excess energy: G6P --&gt; ultimately glycogen via phosphoglucomutase, glucose-1-P uridylyltransferase, glycogen synthase</div>
glycogen synthesis: draw"<img src=""Screen Shot 2021-09-14 at 11.28.54 PM.png""><div><img src=""Glycogenesis-and-Glycogenolysis.jpeg""><br></div>"
circled phosphatehigh energy phosphate
where is glycogen produced?&nbsp;liver and skeletal are only tissues that make appreciable glycogen<div>trace amounts are made in the WAT and kidney</div>
glycogen synthesis (energy requirement and first step from G6P<div>first step: G6P isomerized (switch from C 6 to&nbsp;1 position) (high-energy P)</div> <div>energy cost: 2 high energy phosphate</div>
primary enzymes in glycogen synthesis<div>glycogen synthase: converts glucose as UDP-glucose onto glycogenin (has tyrosine on it!) to make glycogenin-glucose (alpha 1,4 bond).</div><div><br></div><div>branching enzyme: transfers 6-8 glu residues to form an alpha 1,6 bond. (when the chain reaches a certain length).</div><div></div>
glycogen breakdown enzymes (include regulation and associated diseases if applicable)"*glycogen phosphorylase (a and b):* KEY REGULATED STEP that controls synthesis vs breakdown; uses energy from the alpha 1,4 bond and uses inorganic phosphate. makes g1p one at a time from glycogen. Disease: mcardle's disease, enzyme is missing and needs glucose infusions @ night.&nbsp;<i><b>a is active form which is phosphorylated by phosphorylase kinase;</b>&nbsp;<font color=""#f67fe7""><b>b is inactive</b></font></i><div><font color=""#f67fe7""><b><i><br></i></b></font><div>debranching enzyme: cleaves a(1,6) glu glu bonds. mutated in cori's disease --&gt; enlarged liver</div><div><br></div><div>phosphoglucomutase: g1p to g6p, reversible. same enzyme as glycogen synthesis.</div><div><br></div><div>glucose 6 phosphatase: g6p to glucose so it can leave the cell. <b>liver and kidneys only!!! absent from muscle. </b>missing in von gierke's disease, need glucose infusions @ night.&nbsp;</div></div>"
what is the funciton of phosphorylase, glucosyl transferase, and debranching enzyme in glycogen degradation?"<div>phosphorylase (step 1 below): removes the glucose from a chain until there are four remaining&nbsp;</div><div><br></div><div>glucosyl transferase (step 2 below): removes three glucose out of the four remaining from the chain</div><div><br></div><div>debranching enzyme (step 3 below): Last glucose is prevented from cleaving due to steric hinderance – prevents the spontaneous rxn. It removes the last glucose&nbsp;</div><div><br><img src=""Screen Shot 2021-09-15 at 2.33.37 PM.png""><br></div>"
describe how glycogen degredation is activated (start with GPCR and end with phosphorylation of glycogen)"<div>1. Glucagon &amp; epi bind inactive GCPR (bound to GDP). This activates the GCPR via a conformational change, which causes GDP to dissociate and GTP to bind. This converts ATP to&nbsp;cAMP. </div> <div>2. cAMP activates protein kinase A, which activates phosphorylase via phosphorylation, which activates phosphorylase B to phosphorylase A via phosphorylation. Phosphorylase A <span style=""font-weight: bold;"">deactivates </span>glycogen synthase. </div> <div>3. Result: phosphorylation of glycogen and <span style=""font-weight: bold;"">breakdown/glycogenolysis.&nbsp;</span></div>"
PKAprotein kinase A
where are glucagon and epinephrine's targets?"glucagon: liver and adipose, <font color=""#f67fe7"">not muscle</font><div>epinephrine: liver and muscle, <font color=""#f67fe7"">not adipose</font></div>"
G protein in glycogen breakdownreleases GDP, binds GTP and is activated, interacts with AC and activates AC
adenylate cyclase (AC) in glycogen breakdownconverts ATP to cyclic AMP (cAMP) which acts as an intracellular signal
protein kinase A (PKA) in glycogen breakdown"cAMP binds and activates PKA (A for AMP), <font color=""#f67fe7"">turns <b>off </b>glycogen synthesis and PFK2 in liver and WAT and pyruvate kinase in liver all via phosphorylation,</font> turns <b>on </b>phosphorylase kinase via phosphorylation."
what activates PKA?glucagon glucagon glucagon<div><br>***high yield***<br></div>
fructose (disaccharide which includes it, what digests the disac, why is fructose a problem, and how it's formed from cornstarch)sucrose: alpha 1,2 glu-fru<div><br></div><div>digestion: digested by sucrase on enterocyte wall<div><br></div><div>problem: fructose is sweeter than glucose. annual fructose increase went from 0.2 kg/year to 31 kg/year between 1970 to 1997. Fructose also improves shelf stability of foods. It's also cheaper than reg sugar (farm bill 2008).</div><div><br></div><div>cornstarch: hydrolyzed to glucose, but converted by xylose isomerase to 58% glucose and 42% sucrose</div></div>
how does fructose metabolism differ from glucose?"<b>**HIGH YIELD**</b><div><div>Fructose vs glucose: fructose is phosphorylated by fructokinase. Glucose is phosphorylated by hexokinase. Fructose can <span style=""font-weight: bold;"">only be used in the liver. </span>Fructose bypasses PFK checkpoint and is usually converted to fat via fatty acid synthesis.</div><div><br></div> <div>Bottom line: fructose is not responsive to insulin regulation and is converted to fat stores in excess.&nbsp; (at low levels, this isn’t necessarily true). <b>Ultimately produces increased fat stores and insulin resistance.</b></div></div>"
impact of insulin resistancehigher fasting glucose and decreased glucose clearing
fructose increases adiposity because..."<div>1. cheaper than sucrose &amp; potentially lower satiety</div><div>2. rapid intake via GLUT5 (abundant)</div><div>3. cleared by liver directly</div><div>4. fructokinase: efficient</div><div>5. ATP depletion activates AMP deaminase; decreased inhibition of this enzyme by GTP resulted in&nbsp;<span style=""font-weight: bold;"">uric acid</span>&nbsp;overproduction and&nbsp;<span style=""font-weight: bold;"">gout</span></div><div>6. fructose <b>doesn't stimulate insulin***&nbsp;</b></div><div>7. Aldolase B bypasses PFK (F6P --&gt; DHAP and glyceraldehyde), which feeds FA synthesis after being converted to acetyl coa</div><div>8. co-consumed glucose stimulates insulin, promoting FA synthesis&nbsp;</div>"
what does fructose do to hepatic enzyme function? how does it accomplish this?"increases enzyme synthesis via transcriptional control<div><img src=""Screen Shot 2021-09-15 at 3.11.10 PM.png""></div>"
galactose metabolism (disaccharide it's from, digestion, absorption, insulin, and adaptation)<div>disac: lactose: beta 1,4 glu-gal</div><div><br></div><div>digestion: lactase; only beta bond humans can cleave</div><div><br></div><div>absorption: SGLT1 w glucose (active)</div><div><br></div><div>insulin: galactose also doesn’t invoke insulin (like fructose)</div><div><br></div> <div>adaptation: ∆promoter region of gene coding for lactase to&nbsp;genetic lactose-tolerance</div>
galactokinase mutation effect<div>Galactokinase mutations can cause cataracts in the eye, and other enzymes in the pathway</div>
galactokinasegalactokinase or hexokinase, but usually galactokinase (high efficiency) bc hexokinase is usually pretty inactive after eating a meal)<div><br></div><div>galactokinase: galactose --&gt; galactose1P (rate limiting step)</div>
galactose catabolism: draw"<img src=""Screen Shot 2021-09-15 at 3.16.51 PM.png"">"
e27729839af44c859756a1f385d09098-ao-1"<img src=""Screen Shot 2021-09-15 at 2.57.58 PM.png"" />""<img src=""e27729839af44c859756a1f385d09098-ao-1-Q.svg"" />""<img src=""e27729839af44c859756a1f385d09098-ao-1-A.svg"" />""<img src=""e27729839af44c859756a1f385d09098-ao-O.svg"" />"
e27729839af44c859756a1f385d09098-ao-2"<img src=""Screen Shot 2021-09-15 at 2.57.58 PM.png"" />""<img src=""e27729839af44c859756a1f385d09098-ao-2-Q.svg"" />""<img src=""e27729839af44c859756a1f385d09098-ao-2-A.svg"" />""<img src=""e27729839af44c859756a1f385d09098-ao-O.svg"" />"
e27729839af44c859756a1f385d09098-ao-3"<img src=""Screen Shot 2021-09-15 at 2.57.58 PM.png"" />""<img src=""e27729839af44c859756a1f385d09098-ao-3-Q.svg"" />""<img src=""e27729839af44c859756a1f385d09098-ao-3-A.svg"" />""<img src=""e27729839af44c859756a1f385d09098-ao-O.svg"" />"
e27729839af44c859756a1f385d09098-ao-4"<img src=""Screen Shot 2021-09-15 at 2.57.58 PM.png"" />""<img src=""e27729839af44c859756a1f385d09098-ao-4-Q.svg"" />""<img src=""e27729839af44c859756a1f385d09098-ao-4-A.svg"" />""<img src=""e27729839af44c859756a1f385d09098-ao-O.svg"" />"
e27729839af44c859756a1f385d09098-ao-5"<img src=""Screen Shot 2021-09-15 at 2.57.58 PM.png"" />""<img src=""e27729839af44c859756a1f385d09098-ao-5-Q.svg"" />""<img src=""e27729839af44c859756a1f385d09098-ao-5-A.svg"" />""<img src=""e27729839af44c859756a1f385d09098-ao-O.svg"" />"
7a27a7bc440144bb80e814f9f75604a5-ao-1"<img src=""Screen Shot 2021-09-15 at 2.39.11 PM.png"" />""<img src=""7a27a7bc440144bb80e814f9f75604a5-ao-1-Q.svg"" />""<img src=""7a27a7bc440144bb80e814f9f75604a5-ao-1-A.svg"" />""<img src=""7a27a7bc440144bb80e814f9f75604a5-ao-O.svg"" />"
glycogen regulation: draw"<img src=""Screen Shot 2021-09-15 at 2.39.11 PM.png"">"
glycogenolysis: draw"<img src=""Screen Shot 2021-09-15 at 2.36.35 PM.png"">"
f221e74255154575bdf7dff641e94e08-ao-1"<img src=""Screen Shot 2021-09-15 at 2.25.39 PM.png"" />""<img src=""f221e74255154575bdf7dff641e94e08-ao-1-Q.svg"" />""<img src=""f221e74255154575bdf7dff641e94e08-ao-1-A.svg"" />""<img src=""f221e74255154575bdf7dff641e94e08-ao-O.svg"" />"
lipids: two different naming systemsdelta and omega<div><br></div><div>both: numbered based on number of carbons:number of double bonds</div><div>delta: db counted from the inside of the carbonyl</div><div>omega: db counted from the tail of the FA</div>
c04e35bcb0864c42a14b57b7be0dff0d-ao-1"<img src=""Screen Shot 2021-09-15 at 8.24.34 PM.png"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-1-Q.svg"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-1-A.svg"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-O.svg"" />"
c04e35bcb0864c42a14b57b7be0dff0d-ao-2"<img src=""Screen Shot 2021-09-15 at 8.24.34 PM.png"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-2-Q.svg"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-2-A.svg"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-O.svg"" />"
c04e35bcb0864c42a14b57b7be0dff0d-ao-3"<img src=""Screen Shot 2021-09-15 at 8.24.34 PM.png"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-3-Q.svg"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-3-A.svg"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-O.svg"" />"
c04e35bcb0864c42a14b57b7be0dff0d-ao-4"<img src=""Screen Shot 2021-09-15 at 8.24.34 PM.png"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-4-Q.svg"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-4-A.svg"" />""<img src=""c04e35bcb0864c42a14b57b7be0dff0d-ao-O.svg"" />"
<div>draw the unsaturated fatty acids</div>"<img src=""Screen Shot 2021-09-15 at 8.40.14 PM.png"">"
draw the saturated fatty acids"<img src=""Screen Shot 2021-09-15 at 8.40.02 PM.png"">"
which fatty acids are essential?linoleic acid, lenolenic acid, arachidonic acid
cis vs trans significance in FA'strans: food processing -- makes solid at room temperature; by taking liquid fats and removing their fluidity via hydrogenation. trans raise LDL and reduce HDL. rec: &lt;1% of calories from trans fats<div><br><div>cis: naturally occuring form.&nbsp;</div></div>
triacylglycerols (TAGs) functions! (3)- most efficient energy storage bc hydrocarbon dense and water-free<div>- TAGs form core of serum lipoproteins (circulating form of fat energy)&nbsp;</div><div>- are fat-soluble transport agents in blood</div>
phospholipid: draw the structure and draw the four primary substituents on R3"<img src=""Screen Shot 2021-09-15 at 8.50.44 PM.png"">"
inositol phosphate"immune function, pain, inflammation, etc. <font color=""#f67fe7"">Tyenol and NSAIDS interrupt its function</font>"
sterols and steroids (sources, functions, consumption suggestions today)sources: cholesterol (animals; 95% of dietary intake) and plant sterols (only 5%)<div><br></div><div>functions:&nbsp;</div><div>- membrane structure (cholesterol)</div><div>- hormones (vitamin D, sex steroids, glucocorticoids)</div><div>- bile salts (solubilize lipids in digestion)</div><div><br></div><div>consumption suggestion: 350 mg daily (used to be 2x as high!)</div>
three types of dietary lipids to digesttriglycerides, phospholipids, cholesterol esters
How do we enzymatically degrade hydrophobic lipids in a {{c1::hydrophilic}} environment? {{c1::Emulsify}} the lipids with {{c1::bile salts}}.
organs of lipid digestion (simple)mouth, stomach, and small intestine
enzymes and locations of lipid digestionlingual lipase in mouth (cleaves R3)<div>gastric lipase in stomach (cleaves R3)</div><div>pancreatic lipase in small intesting (cleaves R1 and R3)&nbsp;</div>
what is the most significant organ responsible for lipid digestion?small intestine -- 90% of lipid digestion occurs here. cholesterol and fat-soluble vitamins are de-esterified and bile salts convert coarse emulsion into micelles.&nbsp;
pancreatic speed of reaction with regards to:<div>length</div><div>saturation</div><div>carbon #</div>length: long &gt; short<div>saturation: unsaturated &gt; saturated</div><div>carbon #: C1 &gt; C3, &gt;&gt; C2 (very little effect on C2)</div>
pancreatic lipase regulation"<font color=""#f67fe7"">inhibited by bile salts</font><div>enhanced by colipase (also secreted by pancreas); stabilizes and increases hydrophobicity</div>"
pancreatic lipase in lipid digestion<div>TAG's!!</div><div><br></div>TAG --&gt; DAG --&gt; 2-MAG<div>In between each step: uses H2O for hydrolysis and releases one fatty acid</div><div><br></div><div><div>via pancreatic lipase&nbsp;</div><div>(diacylglyceride, 2-monoacylglycerol)</div></div>
phospholipase A2 in lipid digestion<div>Phospholipids!!!</div><div><br></div><div>phospholipid + H2O - fatty acid (from C1 of p-lipid)</div><div>--&gt; product + H2O - fatty acid (from C2 of p-lipid)</div><div>= product which is able to enter the mucosal cellenters</div>
cholesterol esterase in lipid digestioncholesterol!<br><div><br></div><div>reversible rxn, pH dependent. Removes FA in lumen (low pH) and adds FA in mucosal cells (high pH)</div>
three enzymes in lipid digestionpancreatic lipase<div>phospholipase A2</div><div>cholesterol esterase</div><div><br></div><div>for TAG, phospholipids, and cholesterol, respectively</div>
how can lipids get into mucosal cells? (after degredation by appropriate enzymes)micelles, specifically for coarse emulsion particles like cholic acid&nbsp;
bile acids (synthesis, storage, stimulation of release, function)synthesis: by liver from cholesterol<br>storage: gallbladder<div>stimualtion of release: CCK stimulates BA release into small intestine</div><div>function: BA aggregate with lipids to form micelles</div>
glycine &amp; taurine with BAderivatize BA's to lower their pKa and enhance solubility in duodenum (pH 5.8 to 6.5) and allow them to be absorbed
problem with cholesterolcan only be eliminated with bile, meaning it can't be used by the body for energy at all (zero cal)<div>way to remove: block ileal reabsorption w a drug --&gt; exit via feces</div>
how many bile acids are produced in the body per day?20-30 g BA daily
in mucosal cells, what happens to lipids?FFA's DAGs MAGs cholesterol and bile salts are re-esterified to TAG and cholesterol-FA. chylomicrons are made out of these productsand head out of the cell to the lumen <b>except </b>SCFAs which enter the blood.&nbsp;
albumin function (3)- most abundant protein in the bloodstream<div>- buffering capacity for CO2</div><div>- transports hydrophobic substances in the bloodstream&nbsp;</div>
chylomicron structureprimarily TAG, w some cholesterol and phospholipid
{{c1::apoproteins}} on lipoprotein surface {{c2::direct the lipoprotein to its target tissue}}.
sources of FAs for beta oxidation&nbsp;dietary: chylomicrons and free FA's (albumin-bound)<div>postprandial (between meals): VLDLs and stored in adipose tissues (albumin-bound)</div>
beta oxidation is the preferred energy source for the {{c1::heart}} and {{c1::resting skeletal muscle}}.<i>beta oxidation is the secondary energy source for most other tissues (including exercising skeletal muscle)</i>
brain prefers: {{c1::glucose}} &gt; {{c1::ketones}} &gt; {{c1::FAs}}
lipoprotein lipase {{c2::releases C1 and C3 FFA}} from {{c1::TAGs}}. Its function is enhanced by {{c3::ApoCII}}.&nbsp;
The {{c1::liver}} lacks lipoprotein lipase
lipoprotein lipase converts {{c1::TAG}} into {{c1::2 MAG}} and {{c1::2 FFAs}}
Lipoprotein lipase under insulin vs under glucagon/epinephrineinsulin: acts on adipose. FFAs released for TAG storage<div>glucagon/epinephrine: acts on muscle and adipose. enhance FFA supplies for beta oxidation</div>
lipoprotein lipase assists in the release of FFAs from {{c1::TAGs in CMs and VLDLs}}.&nbsp;<div>hormone sensitive lipase assists in the release of FFAs from {{c1::TAGs in adipocytes}}.</div>
hormone sensitive lipase converts {{c1::TAG}} to {{c1::DAG}} and {{c1::FFA}}
intracellular vs extracellular: hormone sensitive lipase is {{c1::intracellular}} only in {{c1::white and brown adipose}} tissues and lipoprotein lipase is {{c1::extracellular in the bloodstream}} and not in {{c1::the liver}}.
hormone sensitive lipase is activated under {{c1::epinephrine}}<i>it is the rate limiting enzyme for FFA release under epinephrine</i>
<i>rate limiting enzyme for FFA release under epinephrine:&nbsp;</i>{{c1::hormone sensitive lipase}}
regulation of hormone sensitive lipase: draw"<img src=""Screen Shot 2021-09-18 at 10.56.03 AM.png"">"
fate of glyceroladipocytes cannot metabolize glycerol (lack glycerol kinase), so glycerol travels to the liver in blood. from there, it can either:<div>1. turn into DHAP and G3P for glycolysis</div><div>2. make glucose using DHAP and G3P via gluconeogenesis</div>
modes of FA diffusion"<div>5 of these</div><img src=""Screen Shot 2021-09-18 at 11.05.50 AM.png"">"
activation of fatty acids: draw, write product name, location, and write enzyme"product: fatty acyl coa<div>enzyme: acyl coa synthetase&nbsp;</div><div>location: cytoplasm or outer mitochondrial membrane</div><div><img src=""Screen Shot 2021-09-18 at 11.08.56 AM.png""><br></div>"
FA transport to mitochondrial matrix: draw, key enzymes in order w function and location"<div>key enzymes in order: acyl coa synthetase, CPT I, translocase, CPT II</div><img src=""Screen Shot 2021-09-18 at 11.10.32 AM.png""><div>acyl coa synthetase: (outer mitochondrial membrane)<br><div><img src=""Screen Shot 2021-09-18 at 11.11.37 AM.png""><br></div></div><div>CPT I and II: (mitochondrial membrane --&gt; mitochondrial matrix)</div><div><img src=""Screen Shot 2021-09-18 at 11.12.24 AM.png""></div>"
fatty acid oxidation steps 1 and 2 with energy and basic drawing"<img src=""Screen Shot 2021-09-18 at 11.13.28 AM.png"">"
energy for palmitate and adding C=C bonds"<img src=""Screen Shot 2021-09-18 at 11.14.13 AM.png"">"
beta oxidation spiral: acyl coa dehydrogenase substrate and product"<img src=""Screen Shot 2021-09-18 at 11.16.04 AM.png"">"
Fatty acids are more {{c1::reduced}} (oxidized vs reduced) than glucose, which makes them have a higher energy yield.&nbsp;
differences with unsaturated fatty acids: beta oxidation (enzymes, energy yield)enolase isomerizes cis double bonds to trans-bond. reductase reduced the bond to one trans bon. each double bond eliminates the generatino of an FADH2 so yields 2 ATP less per double bond.&nbsp;
differences in beta oxidation: odd chain FAs (process, energy yield, requirements)odd FAs are metabolized normally until a 3C fragment, <b><i>propinoyl coA,</i></b> is reached (not acetyl-coa like it is normally!). Three reactions convert propionyl-Coa to succinyl-Coa, which enters the TCA cycle and yields 6 ATPs. (not 12 like it is normally!)<div><br></div><div>1 FADH2 + GTP + NADH</div><div><br></div><div>requirements: biotin, vitamin B12</div>
differences in beta oxidation: short and medium chain FA'sless than 12 in length: short chain. These bypass chylomicrons and are largely cleared by the liver. Malonyl coa is not inhibitory in this case.&nbsp;<div><br></div><div>Cross <b>without </b>the aid of CPT I or II or carnitine. Activated by coa derivatives. 'quick energy' for performance and weight loss.</div>
Alternative fatty acid oxidative pathwaysPeroxisomal beta oxidation: very long chain fatty acids of 24-26 carbons<div>Alpha oxidation: branched-chain fatty acids (in peroxisome). Branched chain FAs are abundant in cow milk and are synthesized in the microbiota. Less than 2% of total FA intake. Increased with gastric bypass and sometimes linked to insulin sensitivity.</div><div>Omega oxidation: yields small amounts of dicarboxylic acids (in ER)</div>
mammals can make all the fatty acids except those with {{c1::double bonds beyond the C9 position}} such as {{c1::linoleic or linolenic acid}}.&nbsp;
mammals cannot make the {{c1::C3 and C6}} double bonds and must obtain these from the diet.
fatty acids can be produced in the following tissues: {{c1::liver, adipose, and mammary gland}}.
how acetyl coa enters FA synthesis: draw"<img src=""Screen Shot 2021-09-18 at 4.12.58 PM.png"">"
draw: citrate transporter"<img src=""Screen Shot 2021-09-18 at 4.19.31 PM.png"">"
draw: malonyl coa synthesis"<img src=""Screen Shot 2021-09-18 at 4.19.50 PM.png"">"
draw: fatty acid synthase function"<img src=""Screen Shot 2021-09-18 at 4.20.34 PM.png"">"
fatty acid synthase complex (function)6 enzymes assemble fatty acids on <b>acyl carrier protein, </b>requiring vitamin B3 and B5. Makes palmitate.
Fatty acid elongase (function)makes longer chain FAs from a pre-existing palmitate. Uses fatty acyl coa.
Mixed function oxidases (aka desaturases) functionAdds double bonds to pre-existing fatty acids. Uses NADPH. CANT MAKE C6 or C3 DB OBVIOUSLY.&nbsp;
malonyl-coa has two distinct regulatory roles: {{c1::increased fatty acid synthesis}} and {{c1::decreased beta oxidation}}.&nbsp;
{{c1::acetyl coa + CO2}} --&gt; {{c2::malonyl coa}}
all tissues that undergo {{c1::beta oxidation}} make malonyl coa
{{c2::Malonyl coa}} inhibits {{c1::carnitine palmitoyl transferase (CPT1)}}.
{{c3::acetyl coa carboxylase}} is inhibited by {{c1::palmitate}} and stimulated by {{c2::citrate}}
{{c3::FA synthase complex}} is inhibited by {{c2::high fat diets and glucagon}} and stimulated by {{c1::a high carbohydrate diet and insulin}}
ACCstwo different ACCs supply malonyl coa for two different needs<div><br></div><div>ACC1: found in tissues that make FAs and TAGs (liver, WAT, and mammary glands). co-localizes with ctirate transporter and citrate lyase. faster for rapid use in FA synthesis</div><div><br></div><div>ACC2: found in tissues that rely on beta oxidation for energy (liver, skeletal muscle, heart -- all tissues in some quantity). co-localizes with CPT1 to limit FA availability for beta oxidation.</div>
In the short term, {{c3::ACC}} is activated by {{c2::citrate}} and inhibited by {{c1::palmitate (end product)}} and {{c1::AMPK}}.&nbsp;"<img src=""Screen Shot 2021-09-18 at 5.13.19 PM.png"">"
In the long term, transcription regulates ACC1 and ACC2. Transcription can be increased by {{c1::a high carbohydrate or low fat diet}} and decreased by {{c1::a high fat/low cabohydrate diet}}.&nbsp;
MetforminPharmacologic regulator of ACC1 and ACC2. It is used in T2DM treatment by improving insulin sensitivity and promoting adipose weight loss. The mechanism of action is not fully clear, but it is supposed that Metformin <b>binds and activates AMPK</b>, inhibiting ACC to reduce FA synthesis through depletion of Malonyl coa.&nbsp;
{{c1::PPARalpha}} is the transcriptional effector of {{c2::fatty acid synthesis}}.
{{c2::PPARalpha}} is induced by {{c1::cortisol}} during {{c1::fasting}} and is activated by ligand binding.<i>Binds upstream sequences of genes to regulate expression; specifically genes encoding for CPT1 and beta oxidation enzymes</i>
PPARalpha binds upstream sequences of genes to regulate expression; specifically genes encoding for {{c1::CPT1}} and {{c1::beta oxidation}} enzymes.
2 routes of TAG synthesis in the liver1. G3PDH (dehydrogenase): reduction of NADH&nbsp;<div>2. GLycerol Kinase: phosphorylation of glycerol via ATP</div>
{{c2::hormone sensitive lipase}} releases free fatty acids from the surface of lipid droplets under hormonal control of {{c1::epinephrine}}.
{{c1::ATGL (adipose triglyceride lipase)}} releases free fatty acids from the surface of lipid droplets under the hormonal control of {{c2::glucagon.}}&nbsp;
TAG storage in adipose tissue"<img src=""Screen Shot 2021-09-18 at 6.38.57 PM.png"">"
ketone synthesis occurs in {{c1::the liver}}
Fat mobilization from adipose TAGs"<div>•<span style=""font-weight: bold;"">HSL</span>:&nbsp;activated by Epinephrine</div> <div>•Ep → cAMP → PKA → phospho-HSL</div> <div>•HSL releases sn-3 FA.</div> <div>•<span style=""font-weight: bold;"">ATGL</span> (adipose triglyceride lipase): more active than HSL, catalyzes same reaction, dominates under glucagon</div> <div>•<span style=""font-weight: bold;"">DAG lipase </span>releases sn-1 FA</div> <div>•<span style=""font-weight: bold;"">MAG lipase </span>releases sn-2 FA</div> <div>•<span style=""font-weight: bold;"">FABP</span> exports FFAs to plasma</div> <div>•FFAs bind <span style=""font-weight: bold;"">albumen</span> and travel to rest of body for energy via β-oxidation</div>"
Fate of TAG glycerol (what hormones dominate, what happens to glycerol)- glucagon and epinephrine dominate&nbsp;<div>- adipose lacks glycerol kinase and can't metaboize glycerol, so WAT exports it into the bloodstream, which is cleared by the liver and is converted either to DHAP and glycolysis (less common) or gluconeogenesis to make glucose for the body (more common)</div>
FFAs are released from {{c2::CMs and VLDLs}} by {{c3::lipoprotein lipase}}. {{c1::Apolipoprotein E}} endocytoses CM remnants.&nbsp;
{{c2::VLDL's}} require {{c1::ApoCII}} as well as {{c1::LPL}} to release FFAs for energy
{{c1::brain, heart, and skeletal muscle}} are the tissues which utilize ketones for energy.
ketogenesis"<img src=""Screen Shot 2021-09-18 at 6.51.30 PM.png"">"
ketone vs FFA vs glucose levels during fasting"<img src=""Screen Shot 2021-09-18 at 6.52.12 PM.png"">"
ketone synthesis: draw"<img src=""Screen Shot 2021-09-18 at 6.53.18 PM.png"">"
Oxidation of ketones: draw"<img src=""Screen Shot 2021-09-18 at 7.00.50 PM.png"">"
what is unique about the liver in the oxidation of ketones?&nbsp;liver cannot oxidize ketones for energy because it lacks thiotransferase (activates acac)
{{c2::ketones}} are taken up by target tissues using {{c1::organic anion transporters (OAT)}}
Ketones and type 1 diabetesPerson cannot make insulin in T1D. Glucagon and epinephrine dominate, but cellular uptake is low (no GLUT4, and HK and GK are saturated).&nbsp;<div><br></div><div>Gluconeogenesis is up-regulated. OAA is low due to excess GNG, so AcCoa is diverted to ketone synthesis.&nbsp;</div><div><br></div><div>Leads to ketoacidosis which can supress brain stem activity and be fatal if untreated.</div>
integrate FA and CHO; quick draw"<img src=""Screen Shot 2021-09-18 at 8.00.36 PM.png"">"
TAG synthesis: draw"<img src=""TAG synthesis.jpeg"">"
fatty acid synthesis: draw"<img src=""fatty acid synthesis.jpeg"">"
beta oxidation: draw"<img src=""beta ox.jpeg"">"
Essential amino acids mneumonic: {{c1::ILWKMVHTF}}
{{c1::Arginine and cysteine}} are essential amino acids <b><i>only in preterm infants.&nbsp;</i></b>
In healthy individuals, the amount of AAs contained in the amino acid pool is {{c1::constant}}. Amino acids are not {{c2::stored in the body,}} they are constantly {{c2::in flux in the amino acid pool.}}&nbsp;
Transamination (draw, function, required cofactors and enzyme, reversibility)"<div>- amino group transfer -- synthesis of nonessential AA's</div>- requires reduced nitrogen and B6 (cofactor)<div>- uses aminotransferase (specific to amino acids)</div><div>- freely reversible rxn</div><div><img src=""Screen Shot 2021-09-18 at 8.25.23 PM.png""><br></div>"
Amino acids eligible for simple transamination (with substrates)alanine (pyruvate)<div>aspartate (oxaloacetate)</div><div>glutamate (alpha ketoglutarate)</div>
serine and glycine synthesis"<img src=""Screen Shot 2021-09-18 at 8.34.28 PM.png"">"
asparagine, glutamine, proline, arginine, and tyrosine synthesis"<img src=""Screen Shot 2021-09-18 at 8.34.50 PM.png"">"
digestion of dietary proteinsstomach: HCl and pepsin breaks proteins down into peptides<div>small intestine: <u>pancreatic proteases</u> (trypsin and chymotrypsin) cleave polypeptides at the peptide bond --&gt; oligopeptides and AA's <b>and </b><u>aminopeptidases</u>&nbsp;(aminopeptidase and carboxypeptidase) which cleave the N-terminal residue from oligopeptides to free AA's.&nbsp;</div>
After absorption into an enterocyte, amino acids can have one of two fates:<div>- a minority, particularly glutamate, are oxidized to liberate energy<br></div> <div>- the majority are passed to the portal circulation</div>
extracellular (portal vein) {{c1::&lt;&lt;}} intracellular concentration of amino acids<i>passive transport out of the mucosal cells, active transport in from the intestine</i>
free amino acids in the intestine are transported into the mucosal cells via {{c1::Na+ dependent transporters}} which is {{c1::active}} transport.&nbsp;
There are {{c1::7 specific}} Na+ dependent transporters for different amino acids, including for the following types: {{c1::acidic, basic, neutral, and proline.&nbsp;}}
absorption of di and tri peptides requires:&nbsp;- cotransport with H+ ions via PepT1 transporter<div>- once inside, requires peptidases to cut down</div><div>- free amino acids enter hepatic portal vein through facilitated transporters</div>
cystinuriamutation in genes responsible for AA transport proteins in kidneys. results in kidney stones, specifically due to buildup of cystine (impaired formation of dibasic AA transporters)
fate of the AA pool&nbsp;TCA, metabolites, glucose, FAs, ketone bodies, steroids, porphyrins, creatinine, purine, pyrimidines, neurotransmitters, N-containing compounds<div><br></div><div>AMMONIA --&gt; UREA in liver --&gt; excreted</div>
{{c1::Tyrosine}} is a precursor for {{c2::dopamine, epi, and norepi}}. Responsible for {{c2::fight or flight response}}.
{{c1::Histidine}} is the precursor of histamine. Responsible for {{c2::immune response, including allergic reactions, and myelin sheath maintenance}}.&nbsp;
{{c2::Tryptophan}} is the precursor for {{c1::serotonin}}. Responsible for {{c1::pain perception, sleep, appetite, temperature, blood pressure, and mood}}.
Amino acids: main controller, how much of dietary AA's are immediately degraded, and what % of AA's are BCAAs.The liver is the main controller of amino acids except BCAA. About 50% of dietary amino acids are immediately degraded, which controls serum AA levels. Approx 70% of free AA's in the liver are BCAAs (branch-chained AA's)
Essential amino acid enzyme activity vs % protein in diet"<div>Increases dramatically w % protein in diet after a certain threshold level. Known as dehydratases.</div><img src=""Screen Shot 2021-09-18 at 8.56.48 PM.png"">"
Nonessential amino acid enzyme levels vs % protein in the diet"<div>increases continuously; no threshold induction; called aminotransferases</div><img src=""Screen Shot 2021-09-18 at 8.57.36 PM.png"">"
Stages of metabolism of amino acids:1. transamination of alpha ketoglutarate to generate glutamate and alpha keto acids --&gt; removal of alpha amino group --&gt; ammonia and alpha-keto acids (carbon skeletons)<div>2. carbon skeletons --&gt; intermediates for energy-producing pathways</div>
function of amino group removal&nbsp;amino group prevents breakdown of carbon skeleton
{{c1::Lysine and threonine}} are the amino acids where transamination is irreversible.&nbsp;
oxidative deamination of glutamate: {{c1::glutamate + glutamate dehydrogenase + NAD+}} --&gt; {{c1::alpha keto glutarate + <b><i>NH3</i></b> + NADH}}. Function: {{c2::primary ammonia source in the liver. Reversible; direction depends on nitrogen}}.&nbsp;
ketogenic AA's: {{c1::WIFYT}} both: {{c1::KL}}
ketogenic AA's produce {{c1::22 ATP + 2 GTP}} as energy<div>glucogenic amino acids produce {{c1::the same amount of energy as glucose, but depending on where the input of an amino acid enters}} as energy</div>
glucogenic amino acids and energy production&nbsp;they <b>do not </b>produce the same amount of energy, because different amino acids enter at various points in the TCA cycle. They are also not broken down at the same rate, for ex, dietary nonessential amino acids are more readily broken down.&nbsp;
treatment for leukemiaasparaginase is a treatment for leukemia because it is involved in the pathway from asparagine to aspartate, which depletes asparagine, an essential element of growth in leukemic cells.&nbsp;
Fate of carbon skeletons (mediating hormones)- carbon skeletons enter the TCA cycle usually, but if we need more energy, some amino acid carbon skeletons enter gluconeogenesis (glucogenic AA's only). Occurs when glycogen stores are depleted. <b><i>MEDIATED BY GLUCAGON</i></b> not epi<div>- carbon skeletons that cannot be used in gluconeogenesis are used for fatty acid oxidation (acetyl coa and acetoacylcoa substrates)&nbsp;</div>
draw: gluconeogenesis w amino acids"<img src=""Screen Shot 2021-09-18 at 9.47.28 PM.png"">"
fate of AA's; fed vs fastedfed:&nbsp;<div>- ketogenic --&gt; acetyl coa --&gt; acetoacetyl coa --&gt; fatty acids (TAGs) or proteins&nbsp;<div>- glucogenic --&gt; pyruvate, OAA, or TCA intermediates --&gt; glucose for glycogen in liver or protein synthesis in muscle</div></div><div><br></div><div>fasted:&nbsp;</div><div>- glucose or ketones</div>
starvation and plasma AA concentration"<div>beginning of starvation: transient early increase of plasma AA's</div><img src=""Screen Shot 2021-09-18 at 9.51.34 PM.png"">"
phenylketonuria"- most commonly encountered AA disorder. Autosomal recessive, most common w irish, turkish, native american ancestry.&nbsp;<div>- Mutation of phenylalanine hydroxylase --&gt; elevated phenylalanine metabolites causes CNS defects, hypopigmentation, and musty malodorous urine.&nbsp;<div>- ID'd by screening at newborn.<br></div></div><div>- Tx: dietary Phe (protein) restriction, tyrosine supplementation, neutral AA therapy, and Kuvan (drug which adds PAH to process phenylalanine manually)</div><div><img src=""Screen Shot 2021-09-19 at 3.51.43 PM.png""><br></div>"
branched chain AA's- essential: leucine, isoleucine, and valine<div>- regulate the mTOR (kinase) pathway</div><div>- catabolism increases FA oxidation and reduces obesity risk</div><div>- improves immune cell function, energy production, and brain function (neurotransmitter synthesis)</div><div>- catabolized by muscle <b>not </b>liver</div><div>- transamination step includes <b><i>branched chain amino acid aminotransferase&nbsp;</i></b></div><div>- oxidative decarboxylation step catalyzed by <b><i>branched chain alpha keto acid dehydrogenase (BCKD) complex</i></b></div><div>- skeletal muscle uses these as an energy source for protein synthesis</div><div>- fasted state: catabolism leads to production of alanine and glutamine which are released by the muscle to stimulate gluconeogenesis</div>
maple syrup urine disease (MSUD)&nbsp;- most common branched chain AA disorder<div>- autosomal recessive</div><div>- cause: deficiency in BCKD complex</div><div>- effect: accumulation of keto acids --&gt; malodorous urine</div><div>- tx: synthetic formula with limited BCAAs to support growth without toxicity. Norleucine supplementation.&nbsp;</div>
Ubiquitin-proteasome system&nbsp;ATP dependent<div>lets a cell know which proteins to degrade by attaching to the protein to be degraded (starting w ubiquitin, then adding the prteasome, degrading the protein for digestion (free amino aicds) and recycling the proteasome and ubiquitin.</div><div><br></div><div>Influenced by: structure and N-terminal residue</div>
Which proteins are more rapidly degraded?Based on N-terminal residue (N-end rule)<div>- Arg, Leu, and PEST sequences (pro, glu, ser, thr): rapid</div><div>- Met, Ser, Pro: slow</div>
Equilibirum constant of transamination rxnsapprox 1, meaning the forward and backwards rxns are almost equal. Helps maintain levels of non-essential AA's available.&nbsp;
ALT and AST"Aminotransferases are intracellular and have low plasma levels.&nbsp;<div>Elevated in nearly all hepatic diseases due to cell necrosis.&nbsp;</div><div>ALT is more specific for liver disease and AST is more sensitive.&nbsp;</div><div><img src=""Screen Shot 2021-09-19 at 1.00.03 AM.png""><br></div>"
oxidative deamination (rxn, location, function, enzyme, cofactors, activators, inhibitors)rxn: liberates amino groups as free ammonia<div>location: liver &amp; kidney</div><div>function: provide alpha keto acids for energy metabolism</div><div>enzyme: glutamade dehydrogenase</div><div>cofactors: NAD or NADPH</div><div>activators: ADP and GDP</div><div>inhibitors: ATP and GTP</div>
ammonia transport to liver for conversion to urea (2 methods!)<div>ONE METHOD</div>glutamine synthetase adds free ammonium to glutamate, forming glutamine. requires ATP. nontoxic transport of 2 ammonia groups on each glutamine. glutamine --&gt; liver.&nbsp;<div><br></div><div>In liver, cleaved by glutaminase --&gt; glutamate + ammonia. glutamate --&gt; ammonia and alpha ketoglutarate (via transamination)</div><div><br></div><div>ammonia --&gt; urea</div><div><br></div><div>ANOTHER METHOD</div><div>transamination of pyruvate in muscle --&gt; alanine to liver --&gt; pyruvate --&gt; glucose (alanine and glutamine carry ammonia to liver)</div>
other sources of ammoniaglutamine (catabolism of branched chain AA's in skeletal muscle<div>intestinal bacteria</div><div>amines</div><div>purines and pyrimidines</div>
urea cycle steps<div>1.Carbamoyl phosphate formation</div> <div>2.Citrulline formation</div> <div>3.Arginosuccinate formation</div> <div>4.Arginosuccinate cleavage</div> <div>5.Arginine cleavage to ornithine and urea</div> <div>6.Excretion of urea</div>
urea cycle regulation&nbsp;"<div>•High protein diet à increased urea production</div> <div>•N-acetylglutamate (#3): <b><i>allosteric activator</i></b> of carbamoyl phosphate synthetase 1 (CPS1)</div> <div>•N-acetylglutamate is formed from acetyl CoA and glutamate, and its synthesis is increased by arginine </div> <div>•N-acetylglutamate increases after a protein-rich meal à <span style=""font-weight: bold;"">↑ urea synthesis</span></div> <div>•<span style=""font-weight: bold;"">Starvation</span> results in use of body protein as energy and thus also increases urea production</div> <div>•Starvation upregulates the expression of urea cycle enzymes</div>"
hyperammonemia"<div>•Usually, capacity of hepatic urea cycle <span style=""font-weight: bold;"">&gt; </span>ammonia generation rate</div> <div>•Liver function compromised = HIGH blood ammonia levels</div> <div>•Direct neurotoxic effect on CNS</div><div><br></div> <div></div> <div><span style=""font-weight: bold;"">Acquired vs. Congenital</span></div> <div>•Acquired: liver disease due to alcohol abuse or viral hepatitis</div> <div>•Congenital: genetic deficiencies in enzymes of urea cycle</div><div><br></div><div>tx: phenylbutyrate, which produces nitrogen containing molecules and assists in clearing waste. binds to nonessential AA's</div>"
creatine phosphate (phosphocreatine)&nbsp;- high energy compound that helps maintain intracellular ATP levels during intense exercise.&nbsp;<div>- synthesis: occurs in liver and kidneys from gly and arg and SAM methyl group. reversibly phosphorylated to creatine phosphate by creatine kinase (ATP)</div><div>- degradation: creatine and creatine phosphate cyclize to form creatinine excreted in urine</div>