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DREXEL / Biology / BIOL 311 / What is the synthesis of glucose from non­carbohydrate precursors?

What is the synthesis of glucose from non­carbohydrate precursors?

What is the synthesis of glucose from non­carbohydrate precursors?


School: Drexel University
Department: Biology
Course: Biochemistry
Professor: Professor louden
Term: Winter 2016
Tags: biochemistry, Louden, and BIO 311
Cost: 25
Name: Biochemistry Final Study Guide with Figures
Description: Overview of the main points for the Final exam and important figures to memorize
Uploaded: 02/11/2016
29 Pages 15 Views 2 Unlocks

Talia Armstrong PhD (Rating: )

I was sick all last week and these notes were exactly what I needed to get caught up. Cheers!


What is the synthesis of glucose from non­carbohydrate precursors?

∙ The synthesis of glucose from non­carbohydrate precursors

∙ Glucose stores are depleted during periods of starvation or fasting beyond a day ∙ Brain relies on glucose as source of energy, glucose must be synthesized from  molecules other than carbohydrates

∙ Reverse of glycolysis

o Pyruvate  Glucose 

∙ 2 Pyruvate + 2NADH +  4ATP +  2 GTP + 6 H2O + 2H+   glucose + 2NAD +   4ADP + 2 GDP + 6Pi DP 

∙ It takes 6 nucleotide triphosphate molecules to synthesis glucose, only 2 are  generated from glycolysis: takes 4 EXTRA molecules to drive unfavorable  gluconeogenesis 

What is the precursor for glycogen synthesis?

∙ Any molecule that can be converted to pyruvate is considered glucogenic o Lactate and Glycerol are glucogenic  We also discuss several other topics like Who is the founder of liberalism?

o The enzymes of glycolysis:

∙  Hexokinase, Phosphofructokinase,  Pyruvate kinase

o The enzymes of gluconeogenesis:

o Pyruvate carboxylase (ATP),  phosphoenolpyruvate (PEP) 

carboxykinase, Fructose 1,6 

What are the antioxidant enzymes?

bisphosphatase, Glucose 6­


o Pyruvate carboxylase: 

∙  metabolically irreversible, uses  biotin as a cofactor, allosterically  activated by acetyl­CoA, anaplerotic  for the TCA cycle (replemishes  OAA), takes place in mitochondria o Phosphoenolpyruvate  If you want to learn more check out What is the purpose of offering an argument?



 Synthesis of PEPCK 

increases in fasting

 Takes place in cytosol

∙ Pyruvate is carboxylated in the mitochondria by pyruvate  carboxylase  

∙ Oxaloacetate cant pass out of the mitochondria ( no transporter  exists), so it is converted to malate which is then converted to  OAA in cytosol  

o Oxaloacetate (OAA) decarboxylated and phosphorylated in  the cytosol by phosphoenolpyruvate carboxykinase  (PEPCK)


∙ Fructose 1,6 bisphosphatase (F1,6BPase):

o Metabolically irreversible reaction  

o F1,6BPase is allosterically inhibited by AMP and fructose  2,6-bisphosphate (F2,6BP)  

o ∙ Glucose 6- Phosphatase: If you want to learn more check out What do places mean?

o Irreversible hydrolysis reaction

o Glucose 6- phosphatase found only in liver and kidney  (pancreas and small intestine)  

o Only those tissues can serve as source of glucose from  gluconeogenesis

o Don't forget about the age old question of How physical impossibility is used to critique pseudoscience?

∙ Glucose 6 Phosphate  

o Precursor for

 Glycogen synthesis

 Glucose synthesis  

o Starting point for the Pentose Phosphate Pathway

o Glucose 6 phosphatase is present only in tissues  

responsible for maintaining blood glucose levels, liver and  kidney  

o In liver, glucose 6 phosphatase is highly regulated  REGULATION OF GLUCONEOGENESIS/GLYCOLYSIS  

∙ Flux through a pathway is controlled at rate limiting steps ∙ Flux through the rate determining steps may be altered by  several mechanisms:

o Allosteric control, covalent modifications, substrate cycles  (futile cycles) and genetic control (enzyme concentrations)  

Glycolysis and gluconeogenesis are reciprocally regulated in the liver  ∙ This prevents both pathways form operating at the same time Don't forget about the age old question of What is the meaning of duration in music?

∙    high AMP indicates  that the energy charge  is low and signals the  need for ATP 

∙ High ATP and citrate indicate the energy  

charge is high and  

intermediates are  


∙ Glucagon stimulates  gluconeogenesis

∙ Insulin stimulates  glycolysis

Substrate (“futile”) cycles and Reciprocal regulation of  glycolysis and gluconeogenesis in the liver: PFK-2, FBPase-2  If you want to learn more check out How is ageism a form of discrimination and prejudice that has negative impacts on all members of society?

∙ Glucagon: through the activation of PKA, phosphorylate  

FBPase2 and PFK2

o Activate FBPase2, inactivate PFK2: favor  

dephosphorylation of fructose 2,6 phosphate to  

fructose 6-P , favor gluconeogenesis

The Cori Cycle: Interaction of glycolysis and gluconeogenesis  

∙ Lactate  





goes to  

liver and is  

made into  


∙ The glucose can go back to the peripheral tissues ∙ Liver uses lipid for energy

Placement of the liver in the circulation :

∙ First pass at removing nutrients absorbed from the  intestine

∙ Can make nutrients available to other major tissues ∙ The liver participates in interconnections of all types  of metabolic fuels

o Carbs, amino acids, fatty acids

∙ The liver regulates distribution of dietary fuels and  supplies fuel from its own reserves  


∙ Overview

∙ 2 stages : oxidative stage and non-oxidative stage

o Important products are as follows:

 Production of NADPH – the pyridine nucleotide used  for reductive biosynthesis  

∙ Fatty acids, cholesterol, nucleic acids  

∙ NADPH also important in elimination of oxygen  


 Formation of ribose 5- phosphate for ribonucleotides ∙ RNA, DNA, coenzymes  

 Mammary glands, liver, adrenal glands, adipose

∙ Not in brain and muscle

 Enzymes of pathway are cytosolic 

Oxidative Stage:  

∙ Produces a 5 carbon sugar phosphate, ribulose 5- phoaphate with production of NADPH (with redox reactions)

∙ NADPH produced by Glucose 6-phosphatase  

dehydrogenase in 1st step of oxidative stage AND by 6- phosphogluconate dehydrogenase in 3rd step of oxidative  stage  

∙ Releases 3 molecules of CO2

Non-oxidative Stage:  

∙ Produces glyceraldehyde 3- phosphate and fructose 6-phosphate

∙ Oxidative Phase: 

Production of 2  

NADPH and ribulose  

5-phosphate from  

glucose 6-phosphate

Functional roles of



-Fatty acid  

synthesis: liver,  

adipose, mammary


synthesis: liver

-Steroid hormone  

synthesis: adrenal,  

ovaries, testes  


Reduced glutathione 

as an antioxidant:  


-Generation of  

superoxide radicals  


microbial activity  

Role of NADPH in RBC:

∙ Oxygen species cause cellular damage  

- production of superoxide (Hb-Fe2+-O2HbFe3+ +O2- - O2+ 2H2O 2H2O2

∙ both O2 and H2O2 can produce reactive free radical  species, damage cell membranes, and cause hemolysis  

Non-oxidative phase: 

∙ Disposes excess pentose phosphates by converting  to glycolytic intermediates  

∙ Series of C-C bond cleavage and formation reactions  o Ribulose 5-P  Ribose 5-P or Xylulose 5-P 

o 2Xylulose 5-P + Ribose 5-P 2 Fructose 6-P 


∙ Trans-ketolase and trans-aldolase have broad  

substrate specificities  

o They catalyze the exchange of 2 or 3 carbon  

fragments between sugar phosphates  

o For both enzymes, one substrate is an aldose,  

one substrate is a ketose  

Denitrification of Superoxide Anion and Hydrogen Perioxide :  

∙ Antioxidant enzymes:

o Superoxide dismutase  

o Glutatione peroxidase  

o Glutatione reductase  

∙ Detoxify reactive oxygen species, generate reducing power, feed  into PPP


Nitrogen Fixation:

∙ Fixation of atmospheric N2  

∙ Performed only by certain prokaryotes  

o Certain free living soil bacteria

o Symbiotic bacteria that live in root nodules in plants ∙ Enzymatic process (nitrogenase complex ), highly conserved  ∙ N2 + 10H+ + 8e- + 16ATP à 2NH4+ + 16ADP + H2 o 1e/2ATP per cycle  

o 2ATP binding shifts reduction potential  

o Fe-S clusters

o Iron

o Molybdenum

o 8 electrons (6 for N2, 2 for H2)

o Electrons are  

transferred from  

pyruvate to  

dinitrogenase via  

ferredoxin and  



o Dinitrogenase  

reductase reduces  

dinitrogenase one  

electron at a time with

6 electrons to fix N2  

and 2 electrons to  

reduce H2  8 total  


∙ Oxygen toxicity to bacterial  nitrogenase: plant derived  


∙ Glutamine Synthetase:  o Catalyzes assimilation

of NH4 into glutamate

to yield glutamine  

o Subunit structure of  

glutamine synthetase (12 identical subunits)  

o Primary regulatory point in nitrogen metabolism.  

Regulation occurs in at least 2 ways:  

 1) Allosteric regulation: Ala, Gly, etc are allosteric  

inhibitors of enzyme. All 8 molecules needed to  

effectively block enzyme activity. Adjusts glutamine

levels according to immediate metabolism  


 2) Covalent modification: adenylation of enzyme  tyrosine residue  

∙ adenylation, covalent, inhibitory  

∙ by Adenylyltransferase (AT)  

Covalent modification:  

∙ adenylylation and deadelylylation are promoted by  adenylyltransferase 

o responds to levels of glutamine, a-ketoglutarate, ATP, Pi  a-ketoglutarate and ATP stimulate uridylylation

 Glutamine and Pi inhibit uridylylation  

∙ anelylyltransferase activity is modulaatedf by bingding to  regulatory protein PII 

o PII is regulated by covalent modification (uridylylation) at  tyrosine residue  

∙ Adenylyltrasferase with uridylated PII (PII-UMP) stimulates  deadenylylation of glutamine synthetase ( activating it ) ∙ Adenylyltrasferase with deuridylated PII stimulates adenylylation  of glutamine synthetase ( deactivates it )

o Uridylylation/deurylylation of PII stimulated by uridylyl transferase 


∙ Amino acid carbon skeletons are derived form 3 general sources:  o Glycolysis, TCA cycle, Pentose phosphate pathway

Precursor: a Keotglutarate

∙ Makes glutamate glutamine, proline, arginine  

∙ biosynthesis for proline and arginine

o major source of arginine produced in urea cycle in  mammals  

o Ornithine L-CitrullineArgininosuccinate Arginine  

Precursor: 3-Phosphoglycerate

∙ Makes serine glycine, cysteine  

∙ Biosynthesis of cysteine from serine in bacteria and  plants  

o Origin of sulfur used for Cysteine synthesis  

 o Adenosine 5’-phsphosulfate (APS) 

 o 3’ Phosphoadenosine 5’phosphosulfate (PAPS) 

 APS and PAPS are the sulfur sources  

∙ Biosynthesis of cysteine from homocystein (intermediate orig. derived from methionine) and serine in mammals  o Homocysteine+serine cysteine  

Precursor: Oxaloacetate

∙ Makes aspartate asparagine, methionine, lysine, threonine

∙ Aspartate to lysine ( 10 steps ): common intermediate (in Lys,  Met, Thr) is aspartate B-semialdehyde

Precursor: Pyruvate

∙ Makes isoleucine, valine, leucine  

Precursor: Phsphoenolpyruvate and Erythrose 4-phosphate  ∙ Makes phenylalanine, tyrosine, tryptophan  

o Chorismate: intermediate in aromatic amino acid  

biosynthesis in bacteria, fungi, and plants- derived carbon  from PEP and carbon from erythrose 4-P  

 Biosynthesis of Tryptophan from chorismate in  

bacteria and plants  intermediate= 5  

phosphoribosyl-1-pyrophosphate (PRPP) 

 Biosynthesis of Phenylalanine and Tyrosine from  

chorismate in bacteria and plants  intermediate =  


∙ Animals can produce Tyrosine directly  

from Phenylalanine via hydroxylation  

∙ Precursor: Ribose 5 Phosphate  

o Makes histidine  

∙   Biosynthesis of histidine in bacteria and plants derived from  PRPP, ATP, glutamine, and glutamate  

Sequential Feedback Inhibition: 

∙ Coordinated regulatory mechanisms in E.coli (asparatate as  precursor)  

∙ Isoenzymes are allosterically regulated  

∙ MAJOR POINT: this type of regulation prevents one end product  from shutting down key steps in a pathway when other products  are required

Molecules Derived from Amino Acids:  

∙ many examples (hormones, coenzymes, nucleotides, antibiotics)   o d-Aminolevulinate 

∙ Mammals: glycine precursor

∙ Bacteria & plants: glutamate precursor  

∙ Heme synthesis from d-aminolevulinate  


∙ Most affected people are heterozygotes (usually asymptomatic)  ∙ “acute intermittent porphyria”: build up of d-aminolevulinate and porphobilinogen can result in abdominal pain and neurological  dysfunction  

∙ many porphyrias ( homozygous state) can cause anemia due to  insufficient heme synthesis  

o treatment: diet, IV administration of heme/derivatives  Creatine:  

∙ In humans, typically half of stored creatine originates from food  ( mainly from meat and fish)  

∙ Endogenous synthesis of creatine in the liver is sufficient for  normal activities

∙ Made from arginine and glycine 

∙ Hydrolysis of phosphocreatine important source of metabolic  energy  


∙ Leads to reducing intracellular environment 

 ∙    Glutamate, cysteine, & glycine are precursors  

∙ Few disulfide bonds in intracellular proteins vs many in  extracellular (antibodies, growth hormone, etc)  

∙ Important in keeping SH groups (cysteines) and Fe2+ (ferrous)

Amino acid decarboxylation leads to amines, often highly  bioactive (e.g. neurotransmitters, vasodilation) ∙ Treatment of ulcers; inhibits secretion of gastric acid:  Tagamet/cimetidine histamine receptor antagonist  

-Polyamines, DNA packaging ( like histones ) come from  ornithine and methionine 

∙ Biosynthesis of nitric oxide 

o Gaseous biological messenger  

o Works by diffusion through cell membrane  

 o Arginine is the precursor  

o Diffusion at short distance.. neurotransmission, blood  clotting, pressure control

DEGRADATION OF PROTEINS AND AMINO ACIDS: CHAPTER 18 ∙ Overview of amino acid catabolism in mammals

∙ Fates of amino group and carbon skeleton take separate but  interconnected paths  

What happens to amino acids once cleaved from larger  proteins?  

∙ Fate of amino group nitrogen of AA:  

o Removed from AA by aminotransferases to yield ammonia  (nitrogen not used in energy-producing pathway)

  Aminotransferases 

∙ In many aminotransferase reactions, a

ketoglutarate is the amino group acceptor

∙ All amino transferases have pyridoxal  

phosphate (PLP) as a cofactor  

∙ Fate of rest of carbon skeleton of AA:

o Enter metabolic pathways as precursors of glucose or  Krebs cycle intermediates  

∙ Fates of ammonium ions

o Some used in synthesis of nitrogen compounds (amino  acids, nucleotides)  

o Excess ammonium ions converted into ammonia, urea, or  uric acid (depends on organism) and then excreted 

Metabolic Fates of Amino Groups:

∙ We derive a small amount of oxidative energy from catabolism of amino acids

∙ Amino acids derived from breakdown of cellular proteins,  ingested proteins, and body proteins (when other forms of fuel  aren’t available)  

∙ Proteases degrade ingested proteins in stomach and small  intestine  

o Early step in catabolism: separation of amino group from  carbon skeleton

 Most cases: amino group transferred to a

ketoglutarate to form glutamate ( requires ryridoxal  


∙ Glutamate: transported to liver mitochondria  

where glutamate DH releases amino group (as  


 Ammonia from other tissues transported to liver as  1) amide nitrogen of glutamine or 2) amino group of  

alanine (from skeletal muscle)  

o Pyruvate produced by deamination of alanine (liver) is  converted to glucose (transported back to muscle):  

glucose-alanine cycle

Amino Group Catabolism:  

∙ Depending on the organism, NH4+ is excreted in different forms  o Most terrestrial organisms ammonia is converted to urea  and excreted: Urea Cycle  

∙ The “Krebs Bicycle” “ links between urea and TCA cycle

∙ Aspartate-agininosuccinate shunt: link the two cycles o Connections more complex than shown: TCA enzymes,  fumarase and malate DH, exist in cytosolic and  

mitochondrial forms  

∙ The glucose-alanine cycle:

∙ Alanine serves as a carrier of ammonia & a carbon skeleton of  pyruvate from skeletal muscle to the liver

∙ Pyruvate produced by deamination of alanine (liver) is converted  to glucose (transported back to muscle)

∙ Ammonia is excreted


∙ Albinism: (lack of pigmentation in skin and hair) - enzyme  = Tyrosine 3 monooxygenase (tyrosinase)  

∙ Alkaptonuria: (dark pigment in urine, arthritis)- enzyme=  homogentisate 1,2 dioxygenase  

∙ Aegininemia: (mental retardation)- enzyme: arginase ∙ Argininosuccinic academia: (vomiting, convusions) –  enzyme= argininosuccinase  

∙ Phenylketonuria: (neonatal vomiting, mental retardation)-  enzyme= phenylalanine hydrolase


Biosynthesis and degradation of nucleotides:  

 ∙     Two biosynthesis pathways: 

o 1) De novo synthesis: “new” synthesis

 Metabolic precursors: amino acids, ribose 5-P, CO2,  and NH3

o 2) Salvage pathway: end products made from “scavenged”  components  

 Recycling of free base and nucleosides produced  

from nucleic acid breakdown  

2 kinds of nucleotides classified by ring structure : 


 ∙     origins of components of ring structure of purines 





∙ multistep pathway that produces important common  intermediate to the synthesis of AMP/GMP- inosinate (IMP)  

Biosynthesis of AMP & GMP: IMP is an important precursor ∙   AMP& GMP are parent compounds of ATP and GTP  ∙   Energy and NH3 group source from ATP and Gln  

Regulation of adenine and guanine nucleotide biosynthesis in  Ecoli.  

∙ 3 major feedback mechanism: PRPP synthetase and glutamine PRPP amidotransferae, adenylosuccinate synthetase, IMP  dehydrogenase – three points of control  

I. De novo synthesis of pyrimidine nucelotides involves asparate,  PRPP, and carbamoyl phosphate 

∙ 6 member pyrimidine ring made first, then attached to ribose 5  phosphate… differs from de novo purine nucleotide synthesis  pathway  

o carbamoyl phosphate first enzyme to start the reaction,  PRPP comes in later  

Bacterial carbamoyl phosphate synthetase:

∙ Has 3 separate active sites

∙ “substrate channeling”: important in limiting  

substrate/intermediates diffusion- multiple steps carried out by  the same enzyme

∙ critical especially if intermediates are unstable  

Bacterial pyrimidine biosynthesis through aspartate  transcarbamolyase (ATCase)  

∙ another example of feedback inhibition

∙ ATCase is first enzyme in pyrimidine de novo synthesis  pathway  

∙ In the presence of CTP it gets larger which tells you that  you need more substrate to reach max velocity  

∙ Negative allosteric control of the enzyme  

Ribonucleotides are precursors of deoxribonucleotides  ∙ Ecoli ribonucleotide reductase 

o Enzyme acts on ribonucleotide diphosphates 

o Reduction involves replacement of 2’ OH group with H o

Regulation of ribonucleotide reductase by dNTPs:  ∙ Primary regulatory site (left) and substrate specificity (effector bound to second regulatory site (right)): idea is to provide a  balanced pool of precursors for DNA synthesis

∙ Both activity & substrate specificity regulated by effector  binding

∙ Enzyme activity:

o ATP activates

o dATP inactivates

∙ Substrate specificity:

o When ATP or dATP is bound: favors reduction of UDP &  CDP 

o When dTTP or dGTP is bound: favors reduction of GDP or ADP, respectively

∙ Thymidylate is derived from dCDP and dUMP

∙ important mechanism of action for drugs- biosynthetic pathway

Degradationof purines and pyrimidines produces uric acid and  urea  

Catabolism of pyrimidines:  

∙ methylmalonyl semialdehyde eventually degraded to succinyl CoA (TCA Cycle)  


∙ Free purine & pyrimidine bases constantly released via metabolic degradation of NTs

∙ Free purines are salvaged and reused to make NTs: one of the  major pathways…

o Adenine + PRPP ----> AMP + PPi

∙ A similar pathway exists for pyrimidines in bacteria and, possibly, mammals

∙ Defect in salvage pathway enzyme (hypoxanthine-guanine  phosphoribosyltransferase: HGPRT) results in Lesch-Nyhan  syndrome 

o Almost exclusive to male children

 o Defective HGPRT results in elevated de novo purine  synthesis & increases in uric acid 

o Symptoms: mental retardation, self-mutilation

∙ Excess urea causes gout, treated with allopurinol, inhibitor of  xanthine oxidase (XO) 

o The oxypurinol generated acts as strong competitive  inhibitor of XO  


∙ Chemotherapeutic agens often target enzymes in the nucleotide  biosynthetic pathway

o Glutamine, azaserine, acivicin

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