USMLE Step 1 Web Prep Glycolysis and Pyruvate Dehydrogenase: Part 1

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Glucose Transport

Glucose entry into most cells is concentration driven and independent of sodium. GLUT 1 and GLUT 3 mediate basal lucose upta!e in most tissues includin brain" nerves" and red blood cells. T#eir #i # affinities for lucose ensure lucose entry even durin periods of relative #ypo lycemia. GLUT $" a lo%&affinity transporter" is in #epatocytes and beta&islet cells. 'fter a meal" portal blood from t#e intestine is ric# in lucose. GLUT $ captures t#e e(cess lucose primarily for stora e. )#en t#e lucose concentration drops belo% t#e Km for t#e transporter" muc# of t#e remainder leaves t#e liver and enters t#e perip#eral circulation. GLUT * is in adipose tissue and muscle and responds to t#e lucose concentration in perip#eral blood. T#e rate of lucose transport in t#ese t%o tissues is increased by insulin.

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Glycolysis

Glycolysis is a cytoplasmic pat#%ay t#at converts lucose into t%o pyruvates" releasin a modest amount of ener y captured in t%o substrate&level p#osp#orylations and one o(idation reaction. Glycolysis also provides intermediates for ot#er pat#%ays. ,n t#e liver" lycolysis is part of t#e process by %#ic# e(cess lucose is converted to fatty acids for stora e. Hexokinase and glucokinase: Glucose enterin

t#e cell is trapped by p#osp#orylation usin 'T-. .e(o!inase is %idely distributed in tissues %#ereas luco!inase is only found in #epatocytes and pancreatic &islet cells.

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Glycolysis

!osp!ofructokinases 0-12&1 and -12&$3: -12& 1 is t#e rate&limitin en4yme and main control point in lycolysis. ,n t#is reaction" fructose 5&p#osp#ate is p#osp#orylated to fructose 1"5&bisp#osp#ate usin 'T-.

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Glycolysis

Glyceralde!yde 3#p!osp!ate de!ydrogenase 6cataly4es an o(idation and addition of inor anic p#osp#ate 0-i3 to its substrate. T#is results in t#e production of a #i #&ener y intermediate 1"3&bisp#osp#o lycerate and t#e reduction of 7'8 to 7'8.. ,f lycolysis is aerobic" t#e 7'8. can be reo(idi4ed 0indirectly3 by t#e mitoc#ondrial electron transport c#ain" providin ener y for

'T- synt#esis by o(idative p#osp#orylation.

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Glycolysis

3# !osp!oglycerate kinase6transfers t#e #i #& ener y p#osp#ate from 1"3&bisp#osp#o lycerate to '8-" formin 'T- and 3&p#osp#o lycerate. T#is type of reaction in %#ic# '8- is directly p#osp#orylated to 'T- usin a #i #&ener y intermediate is referred to as a substrate&level p#osp#orylation. ,n contrast to o(idative p#osp#orylation in mitoc#ondria" substrate&level p#osp#orylations are not dependent on o(y en" and are t#e only means of 'T- eneration in an anaerobic tissue.
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yru&ate kinase6t#e last en4yme in aerobic lycolysis" it cataly4es a substrate&level p#osp#orylation of '8- usin t#e #i #&ener y substrate p#osp#oenolpyruvate 0-9-3.

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Global re ulation is mediated by insulin and luca on. ,nsulin stimulates and luca on in#ibits -12&1 in #epatocytes by an indirect mec#anism involvin -12&$ and fructose $"5&bisp#osp#ate. -12&1 is in#ibited by 'T- and citrate" and activated by ':-. ,nsulin activates -12&$" %#ic# converts a tiny amount of fructose 5&p#osp#ate to fructose $"5& bisp#osp#ate 01$"5&;-3. 1$"5&;- activates -12&1. Gluca on in#ibits -12&$ 0via c':-&dependent protein !inase '3" lo%erin 1$"5 ;- and t#ereby in#ibitin -12&1. -yruvate !inase is activated by fructose 1"5& bisp#osp#ate from t#e -12&1 reaction 0feed& for%ard activation3. .emolytic anemia results from pyruvate !inase deficiency.
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Lactate de!ydrogenase6is used only in anaerobic lycolysis. ,t reo(idi4es 7'8. to 7'8 < by reducin pyruvate to lactate" replenis#in t#e o(idi4ed coen4yme for lyceralde#yde 3& p#osp#ate de#ydro enase. )it#out mitoc#ondria and o(y en" lycolysis %ould stop %#en all t#e available 7'8< #ad been reduced to 7'8.. )#en o(y enation is poor in aerobic tissues 0s!eletal muscle durin strenuous e(ercise" myocardial infarction3" most cellular 'T- is enerated by anaerobic lycolysis" and lactate production increases.
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I*portant Inter*ediates of Glycolysis

8i#ydro(yacetone p#osp#ate 08.'-3 is used in liver and adipose tissue for tri lyceride synt#esis. 1"3&;isp#osp#o lycerate and p#osp#oenolpyruvate 0-9-3 are #i #&ener y intermediates used to enerate 'T- by substrate& level p#osp#orylation.
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Glycolysis in t!e Eryt!rocyte

9ryt#rocytes #ave bisp#osp#o lycerate mutase" %#ic# produces $"3& bisp#osp#o lycerate 0;G-3 from 1"3&;-G in lycolysis. $"3&;-G binds to t#e &c#ains of #emo lobin ' 0.b'3 and decreases its affinity for o(y en. T#e ri #t%ard s#ift in t#e curve is sufficient to allo% unloadin of o(y en in tissues" but still allo%s 100= saturation in t#e lun s.

'n abnormal increase in eryt#rocyte $"3&;-G mi #t s#ift t#e curve far enou # so .b' is not fully saturated in t#e lun s.

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,T

roduction and Electron S!uttles

'erobic lycolysis yields t#ese $ 'T-> lucose plus $ 7'8.> lucose t#at can be utili4ed for 'T- production in t#e mitoc#ondria? #o%ever" t#e inner membrane is impermeable to 7'8.. @ytoplasmic 7'8. is reo(idi4ed to 7'8< and delivers its electrons to one of t%o electron s#uttles in t#e inner membrane. ,n t#e malate s#uttle" electrons are passed to mitoc#ondrial 7'8. and t#en to t#e electron transport c#ain. ,n t#e lycerol p#osp#ate s#uttle" electrons are passed to mitoc#ondrial 1'8.$" and t#en to coen4yme A. @ytoplasmic 7'8. o(idi4ed usin t#e malate s#uttle produces a mitoc#ondrial 7'8. and yields appro(imately 3 'T- by o(idative p#osp#orylation. @ytoplasmic 7'8. o(idi4ed by t#e lycerol p#osp#ate s#uttle produces a mitoc#ondrial 1'8.$ and yields appro(imately $ 'T- by o(idative p#osp#orylation.