NMDF211 Nutritinal Bichemistry Hrmnal regulatin and types f energy metablism Energy Systems Bichemistry Part I Sessin 7 Endeavur Cllege f Natural Health endeavur.edu.au 1
Metablism Metablism includes anablism (build up) and catablism (break dwn). The activity f metablic pathways are regulated accrding t needs in such a way that sme may be stimulated while thers may be suppressed Majr regulating mechanisms 1. Hrmnes (insulin, glucagn, epinephrine, crticsterids, thyrxin) 2. Allsteric enzymes (stimulatin r suppressin by mdulatrs) Mdulatrs 2 types Negative mdulatr reduces activity f the enzyme and slws dwn the rate f reactins Psitive mdulatr increases activity f allsteric enzymes, thus increases rate f reactins Endeavur Cllege f Natural Health endeavur.edu.au 2
Catablic and Anablic Pathways Catablic Pathways Names end in lysis meaning t breakdwn Glycgenlysis Prtelysis Liplysis Glyclysis Glycgen breakdwn Prtein breakdwn Fatty acid breakdwn Glucse breakdwn Anablic Pathways Names end in genesis meaning t create Glycgenesis Glycgen synthesis Prtein synthesis Lipgenesis Fatty acid synthesis Glucnegenesis Glucse synthesis Endeavur Cllege f Natural Health endeavur.edu.au 3
Energy metablism/cellular respiratin Cellular respiratin - the prcess by which chemical energy is released during the xidatin f rganic mlecules. Aerbic respiratin (xygen required) Anaerbic respiratin (n requirement f xygen) Organic mlecules, usually carbhydrate r fat are brken dwn by a series f enzyme-catalysed reactins. Many f these reactins release a small amunt f energy that is channelled int mlecules f a chemical nucletide called adensine triphsphate r ATP (Encyclpaedia f Human Nutritin, 2013) Glucse is metablised int pyruvate (glyclysis) which further frms Acetyl CA. Acetyl CA is further xidised t prduce energy (ATP) Kreb s cycle and electrn transprt chain pathways. Als knwn as energy prductin pathways. Endeavur Cllege f Natural Health endeavur.edu.au 4
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Glyclysis Endeavur Cllege f Natural Health endeavur.edu.au 6
Substrate is glucse. Glyclysis Glucse is xidised t pyruvate in presence f xygen (aerbic glyclysis n t Kreb s cycle) When xygen is depleted, the dminant glyclytic prduct in many tissues is lactate (anaerbic glyclysis frm there nt Cri cycle) Of nte: Red bld cells (RBCs) lack mitchndria and therefre glyclysis is the nly surce f energy metablism. Thus RBCs can nly metablise glucse and nt fats r prteins. Pyruvate can als be prduced frm the amin acids (glucnegenesis) Methinine, Cysteine, Tryptphan, Alanine, Threnine Endeavur Cllege f Natural Health endeavur.edu.au 7
Cellular respiratin and Glyclysis FATS CARBOHYDRATES PROTEINS Fatty Acids, Glycerl Chlesterl Glucse & Other Sugars Amin Acids B1, B2, B3, B5 Pyruvate acetate Ket Acids B1, B2, B3, B5 B1, B2, B3, B5, B6 Nutrient deficiency r dysfunctin can impede this prcess. Acetyl-CA Endeavur Cllege f Natural Health endeavur.edu.au 8
Aerbic Glyclysis Glyclysis (6C cmpund Glucse int tw mlecules f pyruvic acid (3C), which in the cytplasmic slutin becmes pyruvate. Aerbic glyclysis f glucse t pyruvate, requires 2 ATP t activate the prcess, with the subsequent prductin f 4 ATP and 2 NADH Thus, cnversin f 1 mle f glucse t 2 mles f pyruvate is accmpanied by the net prductin f 2 mles each f ATP and NADH. Differences in the amunt f ATP prduced due t different shuttle systems (30 r 32 r 36 r 38). Different calculatins have been used by different Bichemistry bks (Refer BIOB111 Carbhydrates Metablism lecture ntes fr mre details). Glucse + 2 ADP + 2 NAD + + 2 P i 2 Pyruvate + 2 ATP + 2 NADH + 2 H + Endeavur Cllege f Natural Health endeavur.edu.au 9
Glyclysis Cnversin f glucse t pyruvate A ttal f 10 enzymatic reactins that yield 4 ATP 2 Pyruvate 2 NADH Endeavur Cllege f Natural Health endeavur.edu.au 10
Pyruvate t Acetyl CA Each pyruvate mlecule lses a carbxylic grup in the frm f carbn dixide. The remaining tw carbns are then transferred t the Enzyme CA t prduce Acetyl CA. Enzyme Pyruvate dehydrgenase Cfactrs B1, B2, B3, B5, Mg, lipic acid Deficiencies in any f these vitamins can affect energy metablism, as evidenced by the increased cellular pyruvate and cardiac and skeletal muscle weakness in beri-beri caused by thiamin deficiency Surce: Bundless 2013 Endeavur Cllege f Natural Health endeavur.edu.au 11
Tricarbxylic Acid Cycle (TCA Cycle, Citric Acid Cycle, r Kreb's Cycle) Endeavur Cllege f Natural Health endeavur.edu.au 12
The Kreb s Cycle Takes place in the mitchndrial matrix A cmmn metablic pathway fr all fuels Respnsible fr prductin f the majrity f the reduced cenzymes used fr the generatin f ATP in ETC. Participates in glucnegenesis frm amin acids and lactate during fasting between meals and lnger term in starvatin. Intermediates are the surce f mst f the nnessential amin acids such as aspartate and glutamate. Als invlved in the cnversin f carbhydrates t fat fr strage after a carbhydrate rich meal (Encyclpaedia f Human Nutritin, 2013, Energy Metablism). Endeavur Cllege f Natural Health endeavur.edu.au 13
The Oxidative Decarbxylatin f Pyruvate t Acetyl CA require the fllwing enzymes: Thiamin Diphsphate (TDP) - Thiamin (B1) Flavin-Adenine Dinuceltide (FAD) - Ribflavin (B2) Dihydrlipyl Dehydrgenase - Lipic Acid, Mg ++ Dihydrlipyl Transacetylase - Lipic Acid Nictinamide-Adenine Dinuceltide (NAD) Nictinamide (B3) Cenzyme A Pantthenic acid (B5) Endeavur Cllege f Natural Health endeavur.edu.au 14
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Acetyl CA Start Krebs Cycle Acetyl-CA can als be prduced frm fatty acids and frm amin acids r TCA cycle intermediates. Amin acids isleucine, leucine, lysine, tryptphan Acetyl-CA cmbines with xalacetate, frming citrate and releasing the CA fr further reactins with pyruvate t acetyl-ca. A cycle f reactins fllws in which tw mlecules f CO 2 are released and three mlecules f NAD+H + and ne f FADH 2 are prduced alng with ne mlecule f guansine triphsphate (GTP) (equivalent t ATP). At the end f the cycle xalacetate is regenerated and able t react again with anther mlecule f acetyl cenzyme A, and s the cycle cntinues. Endeavur Cllege f Natural Health endeavur.edu.au 16
Explanatin f reactins Unin f Oxalacetate with Acetyl CA frms citrate. The Krebs cycle can becme blcked if ATP levels are adequate at the iscitrate psitin (i.e. n mre energy prductin currently required). The ismerisatin f citrate t iscitrate invlves cis acnitate as an intermediate. The ismerisatin, catalysed by acnitase, invlves dehydratin fllwed by sterically reversed hydratin, resulting in the repsitining f the OH grup nt an adjacent carbn. Iscitrate is dehydrgenated via the Iscitrate dehydrgenase enzyme. The reactin supplies energy via the respiratry chain and its re-xidatin f NADH (B3 dependent enzyme). This reactin is psitively mdulated by ADP and negatively mdulated via ATP. Cfactrs are Vitamin B3, Mg, Mn. Endeavur Cllege f Natural Health endeavur.edu.au 17
Explanatin f reactins Alpha-ketglutarate can be prduced frm the amin acids such as arginine, rnithine, hydrxyprline, prline, glutamate, histidine. The Alpha ketglutarate dehydrgenase cmplex is necessary fr the xidative decarbxylatin f Alpha Ketglutarate t Succinyl CA. Cfactrs are vitamin B1, B2, B3, B5, lipic acid Succinyl CA can be prduced frm the amin acids such as isleucine, valine, methinine The thiester bnd f Succinyl CA, Succinyl Thikinase releases sufficient energy t drive phsphrylatin f Guansine diphsphate (GDP) by inrganic phsphate. The resulting GTP mlecule can nw serve as a phsphate dnr in future phsphrylatin reactins. Cfactr Magnesium The Succinate dehydrgenase reactin uses FAD (B2) instead f NAD as the hydrgen acceptr. Endeavur Cllege f Natural Health endeavur.edu.au 18
Explanatin f reactins The FADH 2 is re-xidised by the electrn transprt f xygen can nly prduce 2 ATP mlecules after cmpleting the xidative phsphrylatin. Fumarate prduced frm the amin acids such as phenylalanine and tyrsine Fumarase incrprates the elements f H 2 O acrss the duble bnd f Fumarate t frm Malate. The cnversin f malate t xalacetate cmpletes the reactin. NAD acts as a hydrgen acceptr in this dehydrgenatin reactin catalyzed by malate dehydrgenase. Oxalacetate can be prduced frm the amin acid aspartate Endeavur Cllege f Natural Health endeavur.edu.au 19
Electrn Transprt Chain r Oxidative Phsphrylatin Endeavur Cllege f Natural Health endeavur.edu.au 20
Electrn Transprt Chain This Chain is the secnd stage f mitchndrial activity. It is made up f fat-sluble enzymes lcated in r within the inner mitchndrial membrane. The jb f the chain is t take hydrgen atms which are carried via the B2 and B3 reactins. The hydrgen mlecule is then cascaded dwn a number f enzyme cmplexes, with the final reactin requiring the utilisatin f xygen t frm water. Reactins take place in fur membrane prtein cmplexes. Endeavur Cllege f Natural Health endeavur.edu.au 21
This pathway is a series f electrn transprters embedded in the inner mitchndrial membrane (crista) that shuttles electrns frm NADH and FADH 2 t mlecular xygen. In the prcess, prtns are pumped frm the mitchndrial matrix t the intermembrane space, and xygen is reduced t frm water. Endeavur Cllege f Natural Health endeavur.edu.au 22
Electrn Transprt Chain Membrane Prtein Cmplexes Cmplex I NADH-Cenzyme Q Oxid-reductase cntains FMN (B2) and 22-24 irn-sulphur (Fe-S) prteins in 5-7 clusters. Cmplex II Succinate Dehydrgenase cntains FAD (B2) and 7-8 Fe-S prteins in 3 clusters and cytchrme b 560. Cmplex III Cenzyme Q-Cytchrme c Oxidreductase cntains cytchrme b, cytchrme c1 and ne Fe-S prtein. Cmplex IV Cytchrme c Oxidase cntains cytchrme a, cytchrme a3 and 2 cpper ins. Endeavur Cllege f Natural Health endeavur.edu.au 23
Activity View YuTube vide at hme t gain greater insight int xidative phsphrylatin here: http://www.khanacademy.rg/test-prep/mcat/bimlecules/krebscitric-acid-cycle-and-xidative-phsphrylatin/v/krebs-citric-acidcycle [accessed 4 th July, 2015] Make yur wn activity table (fr example) Nutrients Amin acid substrates Pyruvate Methinine.. Acetyl CA Alpha-ketglutarate Succinyl CA Fumarate Oxalacetate Endeavur Cllege f Natural Health endeavur.edu.au 24
Electrn Transprt & Oxidative Phsphrylatin Aspartate Oxalacetate Citrate B3 Tyr Phe Nutrient deficiency r dysfunctin can impede this prcess. Malate Fumarate B2, Fe ++ Succinate Mg ++ Iscitrate a-ketglutarate Succinyl-CA Cysteine, Fe ++ B3, Mg ++, Mn ++ B1, B2, B3, B5, Lipic acid Ile Val Met Arg Orn Hy-Pr Pr Glu His NADH CQ 10 Cytchrmes 38 ATPs H 2 O O 2 Endeavur Cllege f Natural Health endeavur.edu.au 25
Summary 1 mle f glucse = 2 pyruvate (2 ATP) + 2NADH (4-6 ATPs) = 6-8 ATPs 6-8 ATPs + Krebs cycle (30 ATPs) = 36-38 ATPs The means that ne mle f glucse generates apprx. 38 mles f ATP The yield f either 6 r 8 mles is dependant n the shuttle system f NADH in the mitchndria fr re-xidatin. If there is a lack f xygen (anaerbic cnditin) the NADH is used in the reductin f pyruvate t lactate, thus nly 4 ATPs will be prduced. Surce: Gregry M 2013, Bilgy Web Endeavur Cllege f Natural Health endeavur.edu.au 26
Questins 1. Glucse can be xidized int which tw prducts? 2. The prductin f these end-prducts is dependent n which factr? 3. What is the name f the cycle which ccurs under aerbic cnditins? 4. What is the name f the prcess by which the NADH is generated in this cycle and used t fuel ATP synthesis? 5. Where des this prcess take place? 6. Hw many ATPs are prduced in cmplete xidatin f glucse? 7. Is there any difference in the amunts f ATP prduced, why? Endeavur Cllege f Natural Health endeavur.edu.au 27
Questins 9. Which amin acids is pyruvate synthesised frm? 10.Which amin acids is acetyl C A prduced frm? 11. Name 3 amin acids frm α-ketglutarate? 12.If the bdy has sufficient ATP, where in the cycle may becme blcked? 13. Which amin acids is fumarate prduced frm? 14.Which 2 nutrients carry the hydrgen atms fr use in the electrn transprt chain? 15.Name the 3 minerals which are needed in this prcess? 16.What are the end prducts f this chain? Endeavur Cllege f Natural Health endeavur.edu.au 28
Glycgen Metablism Glycgenesis Pathway by which glucse is ultimately cnverted int glycgen Endeavur Cllege f Natural Health endeavur.edu.au 29
Glycgen metablism RBCs and brain have an abslute requirement fr glucse fr energy metablism. Glucse is absrbed frm the intestine nly fr 2-3h after a meal. There must be anther surce f glucse t maintain a cnstant bld glucse level. Bld glucse increases after a meal, liver can uptake large amunts f glucse and frms glucse-6-phsphate, where it is used t synthesise glycgen (glycgenesis). When glycgen stres are full, glucse-6-phsphate can enter glyclysis r be used t synthesize glycerl fr the frmatin f fat. Endeavur Cllege f Natural Health endeavur.edu.au 30
Glycgen metablism During fasting between meals, bld glucse levels decrease, glycgen breaks dwn in the liver and glucse released (glycgenlysis). Only liver can release free glucse as muscle tissue lacks glucse-6-phsphatase. The free glucse released by the liver is fr use by the brain and red bld cells. The glucse-6-phsphate released in the muscle tissue frm glycgen can enter directly int glyclysis fr energy prductin by the muscle. Alternatively, it can be metablized t pyruvate and then transaminated t alanine that is exprted frm the muscle t the liver, where it can be used as a substrate fr glucnegenesis. Endeavur Cllege f Natural Health endeavur.edu.au 31
Glycgen Metablism r Glycgenesis Functins Particularly imprtant in hepatcytes Liver majr site f glycgen synthesis and strage 7% f wet weight f liver Als stred in skeletal muscles used as energy surce fr exercise Used as a reserve fr instant energy in general T find ut mre abut glycgen metablism yu can visit this article at hme, available at: http://www.ncbi.nlm.nih.gv/bks/nbk21190/ [accessed 4 th June, 2015] Endeavur Cllege f Natural Health endeavur.edu.au 32
a-d-glucse Mg 2+ Glucse 6-P Glucse 1-P ATP ADP Insulin Glyclysis Glycgenesis 1 2 UTP Glucnegenic precursrs PP 1 3 Cell membrane Glycgenin primer Glycgen (unbranched) 5 Glycgen (branched) 4 UDP-glucse Endeavur Cllege f Natural Health endeavur.edu.au 33
1: Hexkinase/Gluckinase Glucse upn entering cell is 1 st phsphrylated prducing a phsphate ester at n. 6 carbn f glucse In muscle cells the enzyme is hexkinase (mdulated by glucse-6-phsphate) In liver, the enzyme is primarily gluckinase (mdulated by glucse-6-phsphate) Gluckinase can be induced by insulin therefre the liver can reduce bld glucse cncentratins Lw gluckinase activity cntributes t the liver s inability t rapidly take up and metablise glucse Endeavur Cllege f Natural Health endeavur.edu.au 34
2: Phsphglycmutase The phsphate is transferred frm the 6-carbn f glucse t the 1 st carbn by the enzyme phsphglycmutase 3: Nucleside triphsphates Functin as activating substances Hydrlysis f a- -phsphate anhydride bnd f uridine triphsphate (UTP t UMP) Bnding f uridine mnphsphate t the glucse-1-p t frm uridine diphsphate glucse (UDP-glucse) This step stabilises the mlecule t stp sugar frm crystalising (think sugar crystals in sugar as fd) Endeavur Cllege f Natural Health endeavur.edu.au 35
4: Glycgen Synthase Glycgen synthase synthesis s glucse int glycgen with sme prefrmed glycgen (primer) The activity f glycgen synthase is regulated by phsphrylatin f serine residues Glycgenin prtein acts as the primer Glycgen synthase is the primary target f insulin s stimulatin f glycgenesis Endeavur Cllege f Natural Health endeavur.edu.au 36
5: Branching UDP glucse attaches t unbranched glycgen t frm branched glycgen This is an imprtant step as it the glycgen s slubility and cmpactness (i.e. we dn t have t carry big bags f sugar in ur bdy) Makes available many nn-reducing ends f chains s glucse residues can be cleaved and used fr energy glycgenlysis Endeavur Cllege f Natural Health endeavur.edu.au 37
Revisin Questins Where is the majr site f glycgen synthesis and strage? What is the ther majr site f glycgen strage? When glucse enters a cell, what is the first prduct it becmes phsphrylated int? What enzyme undertakes this functin in the liver? What enzyme undertakes this functin in the muscles? During the synthesis f glycgen, why is it s branching structure imprtant? Which imprtant enzyme in glycgen synthesis is the primary target fr insulin? Which amin acid regulates this enzyme s activity? Endeavur Cllege f Natural Health endeavur.edu.au 38
Glycgenlysis Reverse f glycgenesis Stred glycgen back up t glucse when required Endeavur Cllege f Natural Health endeavur.edu.au 39
Glycgenlysis The breakdwn f glycgen int glucse Regulated by hrmnes especially glucagn (frm pancreas and catechlamine hrmnes e.g. Adrenalin/Epinephrine (frm adrenal medulla) Bth stimulate glycgenlysis Therefre it functins as an ppsite reactin (antagnistic) t insulin in regulating bld glucse levels and stred glucse Endeavur Cllege f Natural Health endeavur.edu.au 40
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Glycgenlysis Glycgen phsphrylase can exist as either phsphrylase a (active frm) r phsphrylase b (inactive frm) The rate f glycgen breakdwn depends n the relative activity f these enzymes The enzymes are regulated by 2 ways: 1. Cvalently regulated by adrenaline and glucagn 2. Allsteric regulatin by AMP (ATP cmpetes with AMP - ATP keeps the enzyme in an inactive frm) (S when ATP levels are high, have enugh energy n bard, s need t switch activatin prcess (AMP) ff!) Endeavur Cllege f Natural Health endeavur.edu.au 42
Glycgenlysis Glucse-6-phsphatase nly functins in the liver and kidney nt in muscle cells r adipcytes. Only the liver cntrls the cncentratin f glucse in the bld S muscles cannt cntribute t bld glucse levels. The glycgen in muscles cells and t a smaller extent in the adipse tissue, use the glucse nly within the cells f that tissue (fr its wn use) Endeavur Cllege f Natural Health endeavur.edu.au 43
Summary High intake f sugar cnverted t glycgen fr strage (glycgenesis) Times f increased energy needs (e.g. exercise) glycgen cnverted back t glucse (glycgenlysis) Glucse can then enter glyclysis pathway Endeavur Cllege f Natural Health endeavur.edu.au 44
Questins 1. Which hrmnes regulate glycgenlysis? 2. In the last step f glycgenlysis, which enzyme acts n glucse 6 phsphate t prduce glucse? 3. Where is the nly place that this enzyme functins? Endeavur Cllege f Natural Health endeavur.edu.au 45
Glucnegenesis Term used t describe synthesis f glucse via pathways ther than carbhydrate metablism. May be via several mechanisms Endeavur Cllege f Natural Health endeavur.edu.au 46
Glucnegenesis The bisynthesis f new glucse, (i.e. nt glucse frm glycgen). When dietary CHO a hrmnal triggering f accelerated glucse synthesis frm nncarbhydrate frms ccurs. E.g. Lactate, pyruvate, fat (glycerl) and certain amin acids The prductin f glucse frm ther metablites is necessary fr use as a fuel surce by the brain, testes, erythrcytes and kidney medulla since glucse is the sle energy surce fr these rgans. Synthesis f glucse frm three and fur carbn precursrs is essentially a reversal f glyclysis. The liver is the majr site f glucnegenesis and under starvatin, the kidney s becme invlved Endeavur Cllege f Natural Health endeavur.edu.au 47
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Glucnegenesis Reversal f glyclysis Endeavur Cllege f Natural Health endeavur.edu.au 49
Glucnegenesis Phsphglycerate kinase Only cnsumes energy in glucnegeneis. Glucnegenesis frm pyruvate t 1,3- bisphsphglycerate cnsumes 6 mles f ATP. (Uses a lt f energy) Mst nn-hepatic tissues lack glucse-6-phsphatase and s it wuld be a substrate fr glycgen synthesis. Endeavur Cllege f Natural Health endeavur.edu.au 50
Glucnegenesis In hepatcytes the glucse-6-phsphatase reactins allws the liver t supply the bld with free glucse. Due t a high amunt f liver gluckinase mst f the glucse will be phsphrylated and will flw dwn its' cncentratin gradient ut f hepatcytes and int the bld. Since skeletal muscle lacks glucse-6-phsphatase it cannt deliver free glucse t the bld and underges glucnegenesis exclusively as a mechanism t generate glucse fr strage as glycgen. Endeavur Cllege f Natural Health endeavur.edu.au 51
Questins 1. Frm prducts ther than carbhydrates can glucse be synthesized frm? 2. Which prcess stimulates ketgenesis? Endeavur Cllege f Natural Health endeavur.edu.au 52
Ketgenesis Ketne Bdies Endeavur Cllege f Natural Health endeavur.edu.au 53
Ketgenesis Ketne bdies there are three water sluble cmpunds prduced as by prducts when fatty acids are brken dwn fr energy in the liver and kidneys (Acetyl CA may fllw ther catablic rutes). Ketne bdies are acetacetate, β-hydrxybutyrate and acetne. They serve as an energy surce when glucse is nt readily available. Nrmally, the cncentratin f Ketne bdies in bld are lw but their levels increase during fasting and prlnged exercise. Diabetes is the mst cmmn pathlgical cause f elevated bld ketnes. Endeavur Cllege f Natural Health endeavur.edu.au 54
Ketgenesis Ketne bdies synthesis begins during the first few days f starvatin and as the brain adapts t using ketne bdies as its majr fuel (therefre reducing the need fr glucse) Once enugh ketne bdies are available, glucnegenesis using amin acids which reduces the breakdwn f muscle prtein (sparing effect) After 2-3 weeks f starvatin, muscle reduces its use f ketne bdies and uses fatty acids almst exclusively (leaving the ketne bdies fr the brain) Bth ketgenesis and glucnegenesis are balanced t ensure the efficient use f metablic fuels during starvatin. Glucnegenesis stimulates ketgenesis Endeavur Cllege f Natural Health endeavur.edu.au 55
Glucse Starvatin Graph 50 40 I fed II fasted IIIa early starved IIIb late starved Exgenus I.e. dietary glucse Ttal glucse 30 20 Liver glycgen glucnegenesis 10 0 4 12 20 2 16 40 Hurs Days Endeavur Cllege f Natural Health endeavur.edu.au 56
Explanatin f Graph I Fed state mst glucse is prvided by the diet II Fasted state mst glucse is prvided by the (pst absrptive) breakdwn f liver glycgen stres, amunts are prvided by glucnegenesis III Starved state mst glucse cmes frm glucnegenesis; the breakdwn f prtein and fat. Start f ketgenesis Endeavur Cllege f Natural Health endeavur.edu.au 57
Summary When we need energy glycgen can be cnverted back t glucse (glycgenlysis) Glucse can then enter glyclysis pathway, which eventually frms pyruvate Pyruvate cnverts t Acetyl CA, the starting pint fr the Krebs cycle Krebs cycle creates NADH and FADH, which then enter electrn transprt chain Electrn transprt chain makes ATP we nw have energy! If we dn t have enugh glucse r glycgen t draw frm, the Krebs cycle can still cntinue, but the varius steps (e.g. acetyl CA, pyruvate, citrate etc) are prduced frm varius amin acids which frms part f glucnegenesis Endeavur Cllege f Natural Health endeavur.edu.au 58
Anaerbic metablism Cri Cycle Endeavur Cllege f Natural Health endeavur.edu.au 59
Cri cycle Lactate - generated thrugh anaerbic glyclysis in the muscle - is used fr hepatic glucse synthesis, which then is transprted back t the muscle as an energy substrate. Muscle glycgen (anaerbic glyclysis) t frm pyruvate and lactate. Lactate is then transprted t the liver where it acts as a precursr fr glucnegenesis. Cntributes t apprximately 40% f the nrmal plasma glucse turnver. Advantage f prviding energy (net 3 mlecules f ATP) withut the lss f glucse mlecules. Energy required fr the resynthesis f glucse in the liver is derived frm fatty acid xidatin. The ttal bdy glycgen stres can meet the needs f the brain fr apprximately 3 days. After this perid, alternative surces f metablic fuel must be fund. Endeavur Cllege f Natural Health endeavur.edu.au 60
Cri cycle The Cri cycle pathway allws lactic acid prduced in skeletal muscles during exercise t be cnverted t glucse in the liver by glucnegenesis The glucse frmed can be passed back t muscles via the bldstream t serve as an energy surce Alternatively glucse may be stred in the liver as glycgen Endeavur Cllege f Natural Health endeavur.edu.au 61
Muscular Activity Cri cycle Muscular activity - release f epinephrine r adrenaline by the adrenal medulla. Adrenaline stimulates glycgen breakdwn (glycgenlysis) in muscles and, t a lesser extent, in the liver. Muscular activity quickly uses stred ATP as the energy surce and mre ATP must be generated by the breakdwn f glycgen. Practical example When we start running ften feel sluggish and heavy fr first 10 minutes, and after that starts t feel gd... Because Cri cycle wrks fr abut 1 st 10 minutes, after which imprved circulatin takes xygen t the muscles and aerbic glyclysis becmes main surce f energy Glutamine can be used t prevent lactic acid build up in muscles as it carries lactic acid ut f muscle t liver t be cnverted t pyruvic acid t glucse Endeavur Cllege f Natural Health endeavur.edu.au 62
The Reactin Cascade sequence is as fllws: (in muscle) 1. Adrenaline binds t a receptr n the muscle cell membrane and stimulates adenyl cyclase in the membrane. 2. Adenyl cyclase in the membrane catalyzes the frmatin f cyclic AMP frm ATP. 3. The increase f cyclic AMP activates a prtein kinase. The binding f cyclic AMP t an enzyme is an allsteric cntrl where the enzyme is "switched n" fr activity. 4. The prtein kinase causes phsphrylatins (additin f phsphate) t finally prduce glucse-1-phsphate frm the stred glycgen. Endeavur Cllege f Natural Health endeavur.edu.au 63
The Reactin Cascade sequence is as fllws: 5. At the same time that enzymes are being activated fr glycgen breakdwn, glycgen synthetase enzyme must be inactivated. Glycgenesis must be "switched ff" and glycgenlysis "switched n. 6. Glucse-6-phsphate is the final result f the initial stimulatin by epinephrine r ther hrmnes such as glucagn. If this happened t a muscle cell, then the glyclysis pathway is the next step in the sequence. If this happened t a liver cell stimulated by glucagn, then glucse is prduced t enter the bld stream. Endeavur Cllege f Natural Health endeavur.edu.au 64
Questins 1. In skeletal muscle, which enzyme stimulates the breakdwn f glycgen? 2. What des this initial step frm? 3. What hrmne initiates this prcess? 4. Which enzyme causes the additin f phsphates thrughut the cri cycle? Endeavur Cllege f Natural Health endeavur.edu.au 65
ADDITIONAL RESOURCES The fllwing animatins may help yu in understanding the pathways: Basic respiratin: the cell and energy https://www.yutube.cm/watch?v=_fe5ar1azai Cellular respiratin : Glyclysis part 1 and 2 https://www.yutube.cm/watch?v=jrdjb7id5ly&t=56s https://www.yutube.cm/watch?v=ltig9i3n-jm Kreb s Cycle https://www.yutube.cm/watch?v=xjiypa3hwea Oxidative Phsphrylatin https://www.yutube.cm/watch?v=kgjcm566-my Metablism and Nutritin https://www.yutube.cm/watch?v=kgjcm566-my Endeavur Cllege f Natural Health endeavur.edu.au 66
References Allen, P. (Eds.)(2013). Encyclpedia f human nutritin. Retrieved frm http://www.credreference.cm Depeint, F., Bruce, W. R., Shangari, N., Mehta, R., & O'Brien, P. J. (2006). Mitchndrial functin and txicity: Rle f the B vitamin family n mitchndrial energy metablism. Chemic-Bilgical Interactins, (1-2), 94. Grpper, S. S., & Smith, J. L. (2016). Advanced nutritin and human metablism (7th ed.). Belmnt, CA: Wadswrth Cengage Learning. Hey, L., Strain, J. J., & McNulty, H. (2009). Studies f bimarker respnses t interventin with vitamin B-12: a systematic review f randmized cntrlled trials. The American Jurnal f Clinical Nutritin, 89(6), 1981S-1996S. di:10.3945/ajcn.2009.27230c Hrtn, E. S. (1989). Metablic fuels, utilizatin, and exercise. The American Jurnal Of Clinical Nutritin, 49(5 Suppl), 931-932. Marks, D. B., Marks, A. D., & Smith, C. M. (1996). Basic medical bichemistry a clinical apprach. Baltimre, MD: Lippinctt Williams & Wilkins. Marriage, B., Clandinin, T. M., & Glerum, M. D. (2003). Nutritinal cfactr treatment in mitchndrial disrders. Jurnal Of The American Dietetic Assciatin, (8), 1029. McMurry, J. (1992). Organic chemistry (3rd ed.). Pacific Grve, CA: Brks/Cle Publishing Cmpany. Osiecki, H. (2002). Cancer: A nutritinal/bichemical apprach. Eagle Farm, QLD: Bicncepts Publishing. Endeavur Cllege f Natural Health endeavur.edu.au 67
References Rach, J. (2003). Metablism and Nutritin (2nd ed.). Lndn, England: Msby. Shils M. E., Olsn, J. A., Shike, M., & Rss, A. C. (2006). Mdern nutritin in health and disease (9th ed.). Baltimre, MD: Lippinctt Williams & Wilkins. Stker, HS 2014, General, Organic and Bilgical Chemistry, 7 th edn, Brks/Cle, Cengage Learning, Belmnt, CA. Timberlake, KC 2014, General, rganic, and bilgical chemistry: structures f life, 4 th edn, Pearsn, Bstn, MA. Westman, E. C., Feinman, R. D., Mavrpuls, J. C., Vernn, M. C., Vlek, J. S., Wrtman, J. A., &... Phinney, S. D. (2007). Lw-carbhydrate nutritin and metablism. The American Jurnal Of Clinical Nutritin, 86(2), 276-284. Endeavur Cllege f Natural Health endeavur.edu.au 68
COMMONWEALTH OF AUSTRALIA Cpyright Regulatins 1969 WARNING This material has been reprduced and cmmunicated t yu by r n behalf f the Australian Cllege f Natural Medicine Pty Ltd (ACNM) trading as Endeavur Cllege f Natural Health, FIAFitnatin, Cllege f Natural Beauty, Wellnatin - Pursuant Part VB f the Cpyright Act 1968 (the Act). The material in this cmmunicatin may be subject t cpyright under the Act. Any further reprductin r cmmunicatin f this material by yu may be the subject f cpyright prtectin under the Act. D nt remve this ntice. Endeavur Cllege f Natural Health endeavur.edu.au 69