MCB 450 EXAM 4

a-1,4-glycosidic, a-1,6-glycosidic

in glycogen, most glucose residues are linked via __________________ bonds, and branches are linked via __________________ bonds.

makes it more soluble & allows for faster synthesis/degradation

why is glycogen so highly branched?

non-reducing end

glucose is added to the ___________ end of glycogen.

phosphoglucomutase

converts glucose-1-phosphate to glucose-6-phosphate via transfer of a phosphate group from C1 -> C6

glycogenin

core protein of glycogen which also functions as a primer

glycogen synthase

transfers the glucosyl residue from UDP-glucose to a non-reducing end of the branched glycogen

autoglycosylates at a specific Tyr 194, which contains a terminal hydroxyl group

how does glycogenin serve as a primer in glycogen synthesis?

1. release of G1P
2. remodeling of glycogen for further synthesis & degradation
3. conversion of G1P->G6P

what are the three steps of glycogenolysis/glycogen degradation?

Glucose-6-phosphatase generates free glucose & is present only in the liver (not in the muscle)

why can glucose derived from glycogen be released into the blood only by the liver?

synthesis, breakdown

G6P is a positive regulator for glycogen _____________ and a negative regulator for glycogen ________________.

ATP, glucose

______, ____________ & G6P serve as allosteric inhibitors of glycogen breakdown in the liver.

activates, phosphorylase kinase, breadown

under low blood-glucose conditions, glucagon is released--which _________________ PKA. PKA then phosphorylates & activates _____________________. eventually, glycogen ________________ is stimulated.

inhibits

PKA _____________ glycogen synthesis by phosphorylating glycogen synthase.

protein phosphatases are stimulated, which have the opposite effect of PKA by removing phosphate from glycogen synthase to activate it & therefore the formation of glucose

how do increased glucose & insulin levels activate glycogen synthesis?

inactivate glycogen phosphorylase, which blocks the activation of phosphorylase kinase

how do protein phosphatases inhibit the breakdown of glycogen?

Ca2+ channels on ER open, Ca2+ becomes calmodulin and synthesis is inhibited, breakdown is activated

how does the binding of epinephrine to an a-agonist receptor regulate glycogen synthesis/degradation?

epinephrine

Ca2+, AMP, and ________________ activate glycogen phosphorylase and, therefore, glycogen breakdown in the muscle (during exercise!).

hormonal changes, glucagon levels increase during birth; provides glucose as fuel!

how is glycogen breakdown stimulated during birth? what does this provide for the newborn?

G-6-phosphatase, liver, normal

Glycogen storage disease Type 1a/Von Gierke disease is caused by a lack of __________________ in the __________. this causes an accumulation of glycogen that is _____________ in structure.

type 1b glycogen storage disease

the translocase activity of glucose-6-phosphatase is affected in this glycogen storage disease

Type II: Pompe Disease; massive increased amount but normal in structure

which glycogen storage disease lacks lysosomal a-1,4-glucosidase activity? how much glycogen is found in the affected tissue?

Type III: Cori Disease

deficiency in amylo-1,6-glucosidase debranching activity, causing one to have a swollen abdomen from their enlarged liver. the glycogen amount is increased & the branches are made shorter.

Type IV - Andersen's; a normal amount of linear, unbranched glycogen & leads to cirrhosis

amylo-4,6-glucosidase branching enzyme is defective in which glycogen storage disease? what does this form/cause?

Type V (McArdle's)

this glycogen storage disease is deficient in glycogen phosphorylase & only affects skeletal muscles. the buildup of glycogen is moderately increased and normal in structure.

liver glycogen phosphorylase, Type I, an increased amount

Type VI (HERS Disease) is caused by a deficiency in the ______________________________ enzyme. the clinical symptoms are similar to which other Type? how much/what type of glycogen is found in the affected organ?

Type VII

what type of GSD is caused by defective phosphostructokinase, affects the muscle, and caused an accumulation of normal-structured glycogen?

glucose -> pyruvate -> acetyl CoA -> citrate (transported out) -> acetyl CoA for FA synthesis

how are excess carbohydrates converted into acetyl CoA?

insulin

excess carbs and proteins increase the enzymes whose synthesis is induced by _____________, which promotes FA synthesis

the conversion of acetyl CoA to malonyl CoA by acetylCoA carboxylase

the committed step in FA synthesis is

insulin activates protein phosphatase, which activates ACC; glucagon & epinephrine activate AMPK, which inactivate ACC through phosphorylation

how do insulin/glucagon levels regulate the production of malonyl CoA & its enzyme acetyl CoA carboxylase (ACC)?

cysteine domain (contains SH) & acyl carrier protein (ACP)

what two domains/subunits is the fatty acyl synthase made up of?

4'-phosphopantetheine of CoA

how is the growing FA chain tethered to the ACP subunit of FA synthase?

the use of carnitine transporters: CPTI tranports into the outer mitochondrial membrane where CoA is swapped for carnitine; acylcarnitine is transported into the matrix by CACT; in the matrix, carnitine is swapped back to CoA by CPTII

how are FA transported into the mitochondria?

106 ATP

what is the overall energy yield of B-oxidation?

hypoglycemia, hypoketosis or myoglobinuria

CPT I or II deficiences cause

a molecule of acetate is transferred from acetyl CoA to the -SH group of ACP (forms acetyl-S-ACP)

what is the first step in FA synthesis?

cysteine is activated: the 2C acetyl group is transferred to a temporary holding site (-SH group of cysteine residue)

what is the second step of FA synthesis?

ACP accept the 3C malonate unit from malonyl CoA (the rate-limiting step)

what is the third step of FA synthesis?

malonyl group loses CO2 and is elongated as an acetyl group from cysteine is added

what is the fourth step in FA synthesis?

keto group is reduced to alcohol; B-hydroxybutyryl-S-ACP is formed

what is the 5th step in FA synthesis?

remove hydroxyl by dehydration; formation of crotonyl-S-ACP, with the formation of a double bond bw C2+C3

what is the 6th step in FA synthesis?

reduction of crotonyl-S-ACP into butyryl-S-ACP (double bond is reduced)

what is the 7th step of FA synthesis?

3-7 for 7 cycles; palmitate

what steps of FA synthesis are repeated? what fatty acid is yielded by FA synthase?

C9, linoleic acid

human desaturates cannot introduce double bonds past _____; therefore, we need _______________ in our diet.

Eicosanoids

a-linoleic acids are essential for the synthesis of

OAA (to malate and then to) pyruvate (the malic enzyme reaction)

the cytosolic conversion of __________ to ____________ provides some of the NADPH required for FA synthesis, in addition to the PPP.

glycerol kinase phosphorylates glycerol into glycerol-3-P

how are triacyglycerides synthesized in the liver?

VLDL

___________ transports TAGs into the bloodstream after they are produced in the liver

stored in adipose tissue

in the fed state, when there are high blood glucose and insulin levels, LPL is ___________ and fatty acids are released from TAGs to be ____________

generate energy

in a fasting state, when blood glucose and insulin levels are low (and glucagon is high), fatty acids are used by the muscle and liver to

lipoprotein lipase (LPL)

an enzyme that hydrolyzes triglycerides passing by in the bloodstream and directs their parts into the cells, where they can be metabolized for energy or reassembled for storage.

acyl-CoA synthetase adenylates the fatty acid & produces fatty acyl-Coa

how are fatty acids activated before going in B-oxidation?

oxidation, hydration, oxidation, cleavage

what are the four main steps of B-oxidation/breakdown?

impair oxidation -- not enough carnitine = no ketone bodies = impedes gluconeogenesis = hypoglycemia

how do CPTI/II deficiencies cause hypoglycemia?

excess energy (ATP, NADH & FADH2), malonyl CoA

B-oxidation is inhibited by

inhibits CPT I

how does malonyl CoA inhibit oxidation and stimulate synthesis?

D-B-hydroxybutyrate & acetone

________________ and __________________ are collectively referred to as "ketone bodies"

high acetyl coA concentrations converts acetyl CoA into acetoacetate, and then into D-B-hydroxybutyrate & acetone

how are ketone bodies synthesized in the liver?

conversion of acetoacetyl CoA into HMG CoA by HMG CoA reductase

what is the rate-limiting step of ketogenesis?

thiolase

2 acetyl CoA --> acetoacetyl CoA during ketogenesis

lacks thiophorase, which converts acetoacetate into acetoacetylCoA and then into acetyl CoA

why can't the liver use ketone bodies for energy?

level of ketone bodies can rise much higher bc the fasting state is reached more quickly due to a high muscle/adipose ratio

why are children more susceptible to developing ketosis than adults?

no insulin = no malonyl CoA = unrestricted entry of FAs into the liver to be converted into ketones

why do Type I diabetics develop ketoacidosis?

ACPs, CoA

in FA synthesis, the intermediates are linked to the -SH of ________; in breakdown, they are linked to the -SH of _______.

fed: increased glycogen & FA synthesis
fasting: gluconeogenesis increases
starved: brain adapts to using ketones to spare glucose

how are blood glucose levels maintained during the fed, fasting & starved states?

the synthesis of glucose from molecules that are not carbs -- such as lactase, glycerol & aas (ie. alanine)

what is gluconeogenesis?

liver, renal cortex, renal cortex

during an overnight fast, 90% of gluconeogenesis occurs in the __________ and 10% occurs in the _________________. during prolonged fasting/starvation, 40% of gluconeogenesis occurs in the _________________.

lactate, alanine, glycerol

what carbon substrates are used to make pyruvate for gluconeogenesis?

Cori cycle (anaerobic glycolysis)

the cycle of lactate to glucose between the muscle and liver, particularly during exercise

oxidized, carbonyl

when lactate is converted to pyruvate, the hydroxyl on lactate is ___________ to form the ______________ on pyruvate.

the carbonyl of pyruvate (via alanine aminotransferase)

when alanine is converted into pyruvate, the nitrogen is replaced by

converted to G3P (glycerol kinase), then to dihydroxyacetone phosphate (G3P dehydrogenase)

how does glycerol enter gluconeogenesis?

glycolysis, gluconeogenesis

during ___________________, the pyruvate dehydrogenase complex (PDC) is active; during ____________, it is inactive

acetyl CoA, NADH

high levels of ____________ & ___________ inhibit the PDC.

pyruvate is converted to PEP in 2 steps: pyruvate -> OAA by biotin-pyruvate carboxylase & OAA -> PEP by PEPCK

how is the first irreversible step of glycolysis bypassed in gluconeogenesis?

CO2

biotin serves as a carrier for which molecule?

glyceraldehyde-3-phosphate, dihydroxyacetone phosphate

in (the "second" step of) gluconeogenesis, PEP is converted to ________________ & glycerol-3-phosphate is converted to _______________________.

fructose-1,6-biphosphate

in gluconeogenesis, dihydroxyacetone phosphate & glyceraldehyde-3-phosphate are converted to _________________________ by aldolase.

F-1,6-BIP converts into F6P via F-1,6-bisphosphatase; enzyme is regulated by glucagon signaling

what is the second irreversible step of glycolysis that gluconeogenesis bypasses?

acetyl CoA

the presence of ______________ signals that there is excess energy and, therefore, allosterically regulates & activates pyruvate carboxylase during gluconeogenesis.

lysine

pyruvate carboyxlase contains which amino acid that covalently attaches to biotin?

covalently attached to Lys & contains two catalytic sites: at site 1, bicarbonate is converted to CO2, which reacts w biotin. the long biotin arm swings to site 2, where CO2 is release and OAA is formed

what is the role of biotin in the pyruvate carboxylase reaction of gluconeogenesis?

Multiple Carboxylase Deficiency (MCD)

Group of disorders characterized by deficiency of multiple carboxylases which are all biotin dependent. There exists a biotinase deficiency which cleaves the biotin from lysine, preventing biotin recycling.

fasting-induced hypoglycemia (no PEP = no glucose), lactic acidemia, loss of muscle tone, enlarged liver, "failure to thrive"

PEPCK deficiency causes what types of symptoms?

polarizes the carbonyl of OAA (along with Mn2+) to pulls e-s away from OAA, as well as organizes the gamma P of GTP to be attacked by the C2 oxyanion

what is the role of the arginine finger in the PEPCK mechanism?

via transcription; a TF that triggers all other responses elements & TFs; insulin destroys FOXO1 via phosphorylation and therefore prevents transcription of PEPCK

how is PEPCK regulated? what is FOXO1 and what is its role? what role does insulin play?

pyruvate kinase is inactivated (phosphorylated form) through glucagon, ATP, acetyl CoA, alanine and FAs

how is futile cycling (the conversion of PEP back into pyruvate) prevented during gluconeogenesis?

inhibits gluconeogenesis & stimulates glycolysis: inhibits the conversion of F-1,6-BIP to F6P in gluconeogenesis

how does Fructose-2,6-biphosphate reciprocally regulate gluconeogenesis & glycolysis?

inhibits/reduces

glucagon __________________ fructose-2,6-bisphosphate

conversion of glucose-6-P to glucose by glucose-6-phosphatase (enzyme is stimulated by glucagon and inhibited by insulin)

what is the third irreversible step of glycolysis that gluconeogenesis bypasses?

Von Gierke's Disease

glucose-6-phosphatase deficiency characterized by hypoglycemia, enlarged liver, lipidemia & lactic acidosis

NADH increases in liver, causing the intermediates of gluconeogenesis to be diverted to alternate reaction pathways to detoxify the ethanol -- causing decreased glucose production

how does alcohol intoxication impair gluconeogenesis and lead to hypoglycemia?

impairs the conversion of lactate to pyruvate, increasing lactic acid levels

how does alcohol consumption lead to lactic acidosis?

excess glucagon secretion induced by starvation

how does alcohol lead to hyperlipidemia?

without carbs (and the ^ energy produced by gluconeogenesis), our bodies rely on fat breakdown for energy to meet the ATP demand

how do low-carb diets lead to fat loss?

anaplerotic: synthesizing/replenishing intermediates of TCA cycle
cataplerotic: intermediates leaving TCA cycle into gluconeogenesis

what is the difference between anaplerotic and cataplerotic reactions?

E1: pyruvate dehydrogenase
E2: dihydrolipoyl transacetylase
E3: dihydrolipoyl dehydrogenase

what are the 3 enzymes that make up the PDC?

substrate channeling

the intermediates of the five-step PDC reaction never leave the complex

TPP (thiamine pyrophosphate), Vitamin B1 (thiamine)

E1 requires which coenzyme/prosthetic group/vitamin?

Lipoic acid (lipoamide)

E2 requires which coenzyme/prosthetic group?