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Flashcards in Biochemistry Deck (63):
1

Glycolysis

Begins with G-6P that is then shuttled to make NADH and GTP by substrate level phosphorylation
-Generates pyruvate that can enter the TCA cycles as Caetyl CoA
-Rate limiting step is PFK-1
-Occurs in cytosol, only means of energy in RBC
-PK deficency leads to hemolyitc anemia in newborns most commonly, can't maintain membrane
-High energy inhibits, but is overcome by F26 in liver
-High energy stimulates GNG

2

PFK-1

-Activated by F2,6BP which is generated by PFK-2 that is activated by insunlin. Increase intermediates in TCA to become anabolic
-Inhibited by low levels of F26P and also by high levels of citrate (Substrate feedback)
-Glucagon increases activtiy of phsophatase that decreased 2,6 BP levels

3

Pyruvate

-Can Enter the TCA cycle as acetyl CoA through Pyruvate dehydrogenase
-Can become alanine using B6 and ALT
-Can become Lactate using LDH (Generate NAD)
-Can enter GNG through Pyruvate carboxylase in the mitochondria (biotin)

4

PDH

-Transform Pyruvate into aceetly CoA for the TCA cycle
-B1,2,3,5, lipoic acid
-Inhibited by arsenic (lipoic acid)
-X linked defects can lead to neurologic symotoms
-Must reduce flux through glycolysis and increase ketones
-Leucine and Lysine are ketogenic AA

5

TCA

-Generate NADH and GTP to be used in ETC also entry and exit for other substrates
-OAA added to acetyl CoA generates citrate (Citrate synthase)
-Alpha ketoglutarate requires same comfactors as PDH: 1,2,3,5,lipoic acid
-generates succinyl CoA and NADH
-Succinyl CoA also produced by odd chain FA metabolism (B12)
-Fumarate is entry of urea cycle

6

ETC

-FADH enters later
-NADH earlier
-Inhibited by Cyanide (can't pass e in Fe) treat with oxidation of RBC and thiosulfate (nitrates)
-Also DNP, aspirin, brown fat are uncouplers

7

GNG

-Pyruvate carboxylase in Mito generats OAA from pyruvate, requires biotin
-OAA goes to PEP by PEPCK
-F1,6BPase is rate limiting, activted by energy and inhibited by F26BP
-G6Pase in Er allows for liberatino, defect in von gierkes disease
-Odd chain FA can enter at malonyl CoA
-Glycerol can also contribute

8

HMP shunt

G6P to generate NADPH and ribbulose 5 P
-Defects in G6PDH lead to decreased NADPH and decreased substrate for glutathione to be reduced leads to oxidative damage of RBC (oxidative and nonreversible portion)
-Also can generate F6P that can re-enter glycolysis, non oxidative and reversible. Thiamin is the cofactor and transketolase activity can monitor thiamine levels

9

Oxidative Burst

-NADPH oxidase is used to oxidize oxygen
-Myeloperoxidase can then couple to Cl and generate bleach
-Defect is impaired killing leading to S Aureus, PSeudomona, Aspergillus, Serattia infections
-Glutathione is crucial for reducing excess free radical production.
-Defect in G6PD can also lead to a decresed effectivness of oxidative killing
-Treat with IFN gamma

10

essential Fructose uria

-Defect in fructose kinase
-Inconsequential
-Will not have glucose in the urine, but will have reducing sugar in urine

11

Fructose Intolerance

-Defect in Aldolase B AR
-Converts F1P to DHAP/GAP
-Accumualtion of trapped F1P
-Jaundice, hepatomegally, failure to thrive and cirrhosis
-Aldolase B which gets rid of trapped fructose

12

Galaktokinase Def

-inability to trap glactose in cells follwoing
-Galactose can accumlate and be converted by aldose reductase to galacticol and accumlate in eyes leading to cataracts

13

Classic galactosemia

-Loss of galactose 1 uridyl transherase leads to an accumulatin of galactose 1 P in cells that can't get our
-Failure to thrive, cirrhosis, jauncide. aplso an accumulation of galactose in blood leds to neonatal cataracts

14

Sorbitol

-GLucose can be trapped by aldose reductase in all cells
-Most cells contain functional sorbitol dehydrogenase, if they dont, accumulation leads to osmotic damage
-This is the same process as diabetes, the retina, schwann cells, and kidney don't have sorbitol dehydrogenase (Enters at fructose)

15

Essential Amino Acids

Ones that are not used elsewhere
-Ketgenic are Lysine and Leucine
-His and Lys are in histones
-Gluc are His, Met, Val

16

Phenylalanine

-Phenylalanine hydroxylase generates tyrosein (BH4)
-Tyrosine generates Dopa (BH4)
-Dopa generates dopamine (B6)
-Dopamine generates Norepi (C)
-Norepi generates Epi (SAM)
-Dopamine - HVA
-Norepi -MVA
-Epi - Metanephrines
-all use SAM

17

Tryptophan

-Generats Niacin using B6
-Generates Seretonin using B6 and BH4, seretonin can then genarate melatonin

18

Histadine

Histamine B6

19

Glycine

Phorphyrin (B6) and Heme

20

Glutamine

-Gaba (B6)
-Glutathione (gltaminc acid, glycine and cysteine) free radical scavenger

21

Asparagine

-NO
-Creatanine
-Urea

22

Urea Cycle

-N-acetylglutamine (Acetyl CoA and glutamine) is cofactor for carbamoyl phosphate synthase 1 which takes NH3 and CO2 and generates carbamoyl phosphate
-CP then enters urea cycle and bind to ornithine (OTC) to generate cituline
-Aspartate enters urea cycle and adds NH2 to generate arginosuccinate
-Arginosuccinate then split into fumarate (enters TCA) and arginine
-Water aded to argenine to make urea (Arginase) and ornithine
-Net is 2 NH4 recycled to urea, fumarate added to TCA

23

Ammonia Transport

Amino acids add NH3 group to alpha ketoglutarate to generate glutamate
-Glutamate then donates NH3 to pyruvate to generate Alanine
-Alanine transported in blood to liver where NH3 is removed by ALT (B6) and complexed to alpha ketoglutarate to generate glutamate which can then donate to urea cycle
-Urea cycle happens exclusively in the liver and all NH3 needs to be transporteed there in this manner

24

Hyperammoniemia

-Elevated levels of ammonia reduce cellular levels of alpha ketoglutarate and shut down TCA cycle
-Caused by a defect in urea cycle
-Leads to asterixis and brain problesm
-Can treat with Benzoate, phenylbuteride that bind to AA and prevent absorption
-Can also give laculose that will cause GI acidification leading to trapping of NH4 in GI

25

N-Acetylglutamine

Necessary for transfer of amino groups via CPS1
-Defect leads to ammonemia

26

OTC Def

-X linked defect in OTC that leads to an increase in carbampyl phosphate and a decrease in citurlline and a halting of urea cycle
-Present with ortoic aciduria, decreased BUN and increased ammonia that leads to signs in brain. There will be no anemia like is seen in orotic aciduria

27

Phenylketonuria

-Defect in Phenulalanine hydroxylase which elads to an accumlation of phenylalanine and an increase in phenyl jetones
-Prenatal screen at 2-3 days due to maternal enzyme function during uteri
-If maternal does not maintain dietary control can get syomptoms in child (microcephaly and retardation)
-Tyrosine become essential
-Also due to BH4 synthase defect, malignant, can't metabolize a number of AA including tyronse

28

Tyrosine metabolism

-Tyronsinase generates melanin (BH4) (albanism)
-Homogentisic opxidase metabolizes metabolite to enter TCA cycle

29

Alkaptonbuira

-Defect in homogentisic oxidase leads to accumlation of homogentisic acid which is balck incolor
-Can cause arthtis
-Tyrosine emtabolites can't enter TCA cycle

30

Urea Cycle

-Carbamoyl phosphate uses N-actelglutamine as cofactor and take NH4 and CO2 to generate CP that combines with ornithine (OTC) to generate citrulline. Addition of aspartate (NH4 gourp) generates arginosuccinate that then gives off funmarate to enter the TCA cycle and generates Arginine
-Arginase splits of urea roup with water and generates ornithine to recycle

31

Amino acid transport

-Tissue add NH3 to alpha ketoglutarate to generate Glutamine that then donoates to pyruvate to generate alanine that is moved in blood to liver wehre reverese happens, take off NH3 and add to alpha ketoglutarate to generate Glutamine taht is then used in the urea cycle

32

Homocystinuria

-Homocysteine can become methionine with B12 and methionine methyl transferase
-Homocysteine can become cystathione and then cystiene with B6 and cystathione synthase
-Defect in MMT treat with increase methinonine
-Defect in CS leads to decrease cysteine. Decrease methionine and icnreae cysteine
-Also can be decreased affinity of CS for B6, treat with high dose B6
-In all cases elevated homocysteine leads to many marfanoid feature, intellectual disability, homocystinuria, premature athereosclerosis and MI
-Can also occur due to a decrease in dietery Folate or B12, treat that first

33

Cystinuria

-Defective transporter of basic AA in PCT leads to accumulatino in filtrate. Cysteine becomes Cystine dimers that are large staghorn calculi
-Treat with fluids and alkalinzatino of urine (Acetazolaminde/K citrate)
-Urinary cyanide nitroprusside test is positive

34

Mapple Syrup Urine Disease

-Defect in alpha ketoacid dehydrataase leads to impaired ability to degrade BCAA
-Leads to accumulation in blood and urine that smells like maple syrup
-Neurotoxic leading to ID and death
-Cofactor for enzyme is thiamine, so high dose thiamine and decrease in BCAA consumption are treatment options

35

Cystinuria

Test with urinary Cyanide Nitroprusside test

36

MSUD

-Thiamine is cofactor for alpha ketoacid dehydratse
-Treatment is high dose thiamine and decreased intake

37

Glycogen Regulation

-Insulin increases glycogen synthase activity which convets UDP glucose to glycogen by adding 1,4 linkages
-Glucagon and B receptors lead to increae in PKA that leads to a decrease in glycogen synthase and an increase in phosphyrlas
-Ca and alpha receptros (Gq) increase activity of phosphyrilase

38

Glycogen synthesis

-Glucose 6 P converted to glucose 1 which is then UDP added that can then be converted to glycogen by glycogen phosphorylase
-Glycogen made in 1,4 linkages and 1,6 linkages at branch points

39

-Glycogen breakdown

-Glycogen phsophorylase breaks 1,4 bonds
-Debranching enzyme breaks 1,6 bonds

40

Von Gierkes Disease

-Defect in hepatic glucose 6 phosphatase
-Leads to inabilty to liberat glucose from liber
-fasting hypoglycemia and lactic acidosis with hepatomegally

41

Pompe's disease

-Accumualtin of alpha 1,4 glucose in lysosomes leading to Cardiomegally and death

42

Cari disease

Debranching enzyme deficency leads to mild fasting hypoglycomia and lactic acidosis
-Hers disease is a problem with hepatic glycogen phosphyrlase

43

McArdle dsiease

-Problem with muscle glycogen phosphorylase leads to inability to breakdown glycogen in muscle when needed
-Severe exercise intolerance and myoglobinuria with severe cramping
-Can also cause electrolyte abnormalities that lead to arrythmias

44

Fabry's Disease

X lnked defect in alpha galactosidase that leads to peripheral neuropathy
-Also renal and CV problems and angiokeratomas
-Only XLR of lyososmal storage disease
-Accumulation of ceramide trihexodside

45

Gaucher's disease

-AR defect in glucocerebrosidase
-Leads to accumulation of glucocerbroside most notably in bone macrophages
-Leads to pancytoenia and bone pain with necrosis, also HSM

46

Niemann Pick

Defect in sphingomylinase leads to accumulation of sphingomyelin
-HSM and cherry red spot

47

Tay Sachs

-Defect in hexosamindase A elading to accumulation fo GM2 ganglioside
-Cherry red spot without HSM

48

Krabbe

-Defect in galactocerebrosidase
-Peripoherl neruropathy, optic atrophy and globoid cells

49

Metachromatic leukodustrophy

Defect in aryl sulfatase leads to sulfatide accumulation
-Widespread demtylinatin, dementia and ataxia

50

Hurler

-AL iduronate sulfatase
-Leads to accumulation of heparan and dermatran sulfate
-Gorgoyle facies, progessive decline and corneal clouding

51

Hunters

XR milder form of Hurlers
-no corneal clouding, aggressive behavior adnd coarse features

52

Pompe's disease

Defect in lysosomal degredation of alpha 1,4 galactosidase which leads to accumulation in heart and other tissues
-Heart failure is cause of death

53

Fabry's

Galactosidase A leads to peripheral neuropahty
-Renal and CV deposits and angiokeratomas

54

Krabbe

Galactocerebrosidase
-Peripheral neuropathy, optic atrophy, globoid macrophages

55

Fatty Acid metabolism

-Carnitine is essential carrier to get into and out of mitochondria

56

FA breakdowns

-Generate Acetly CoA that can be used in TCA cycle

57

FA synthesis

-Use acetyl CoA carboxylase to generate Malonyl CoA that can be used to add 2 carbons at a time to generate palmitate

58

MCAD

Defect in the ability to break down medium chain fatty acides
-Leads to fasting hypoglycemia (no glycerol or energy)
-There will also be an increae in C8 and C10 in blood

59

Carnitine Deficency

-Can't get FA into or out of mitochondria
-Weakness and hypoketotic hypoglycemia
-Hypoketeotic hypoglycemia

60

Acyl CoA dehydrgoenase Deficency

Can't breakdown Acyl FA leading to a decrease in the amoutn of Acetyl CoA
-Acetyl CoA is necessary allosteric activaotor of Pyrvate carboxylase
-Decrease Acetyl CoA means GNG stops
-Fasting hypoglycemia

61

Ketones

-Acetoacetone and beta hydroxybutyrate are synthesized from HMG CoA and can be sent into blood
-Can enter brain and muscle wehre they will be broken down into two molecules of acetyl CoA for energy

62

Starvation

-OAA from TCA is shuttled to GNG meaning Acetyl CoA will accumulate. This accumulation will lead to ketone production via HMG CoA

63

Alcoholism

-Increase in NADH to NAD ratio leads to loss of OAA in OAA/Malate shuttle
-Excess Acetyl CoA is made as ketones