Fructose, Galactose Metabolism - Abali 3/9/16

Question 1

C₆H₁₂O₆ molecules and relationships with each other

Answer 1

glucose, galactose, fructose, mannose

• isomers: same chem formula: all are isomers of one another
• epimers: vary in config around ONE non-carboxyl group C
  
  • glucose & galactose : C4 epimers
  • glucose & mannose: C2 epimers
• enantiomers: L- and D- are mirror images
  
  • biologically active sugars are Ds

Question 2

ring structure of monosaccharides

Answer 2

aldehyde (keto) group reacts with hydroxyl group of the same sugar

• rings can open and reclose → can get rotation about C with reactive carbonyl group (anomeric C) → distinct alpha and beta configs (anomers)

Question 3

key mono-, di-, polysaccharides

why is sucrose special?

Answer 3

monosacchs: glucose, fructose, galactose

disacchs: maltose (glucose+glucose), sucrose (glucose+fructose), lactose (galactose+clucose), trehalose (glucose+glucose)

• sucrose has both anomeric carbons fixed in a glycosidic bond

polysacchs: glycogen, starch, cellulose

Question 4

polyol pathway for fructose synthesis

Answer 4

present in many tissues (hepatocytes, ovaries, sem vesicles), not well understood in all

• seminal vesicles: synthesizes fructose for seminal fluid

glucose → sorbitol → fructose

Question 5

DM2 and sorbitol

Answer 5

diabetes: insulin def/resistance. cells that are not regulated by insulin experience glucose accumulation (kidney, lens, retina, etc)

glucose → sorbitol [aldose reductase]

• doesnt happen under normal conditions; does in DM2

sorbitol accumulation in cells that lack sorbitol DH (kidney, lens, retina, Schwann cells)

• sorbitol is osmotically active → influx of water, cell swelling
• retinopathy, cataracts, periph neuropathy

Question 6

fructose metabolism

Answer 6

fructose enters int epi cell through GLUT5, leaves through GLUT2

in liver: fructose → F1P [fructokinase]

extrahepatic tissues: fructose → F1P [hexokinase]

F16 splits into 3C molecules → DHAP + glyceraldehyde [aldolase B - rate limiting]

glyceraldehyde → glyceraldehyde3P [triose kinase]

yields 2 precursors of TAG synthesis!

• glyceraldehyde → glycerol [glycerol DH] → glycerol3P [glycerol kinase] + FAs → TAGs
• glyceraldehyde3P →→→ pyruvate → acetyl CoA → FAs + glycerol3P → TAGs

Question 7

hereditary deficiencies in fructose metabolism

Answer 7

essential benign fructosuria : fructokinase def

hereditary fructose intolerance (HFI) : aldolase B def

Question 8

aldolase B

Answer 8

enzyme catalyzing rate liiting step in fructose metabolism (low affinity for F1P)

fructose 1P → DHAP + glyceraldehyde

normally, a fructose-rich meal leads to fructose accumulation in liver while slow degradation turns them into glycolytic intermeds

• individuals with HFI (aldolase B def) accumulate higher levels of fructose than normal

Question 9

essential fructosuria (benign)

Answer 9

fructokinase deficiency

• autosomal recessive (1/130k)
• benign, asymptomatic
• fructose accumulation in urine

Question 10

hereditary fructose intolerance

Answer 10

aka fructose poisoning

aldolase B deficiency → intracellular trapping of F1P

sx: P on fructose “takes up space” that would be taken up by inorganic P, leading to…

• severe hypoglycemia, jaundice, hemmorhage, hepatomegaly, hyperuricemia

tx: detection, rapid removal of fructose/sucrose from diet

Question 11

HFI, F16 buildup, consequences of it

Answer 11

aldolase B deficiency → F1P buildup

P on fructose “takes up space” that would be taken up by inorganic P, leading to hypoglycemia

how?

• glycogenolysis inhibited by lack of P (glycogen → G1P)
• gluconeogenesis inhibited by lack of aldolase B (and its comp inhibition by F1P)
• lactic acidosis sets in

Question 12

galactose metabolism

Answer 12

G1P uridyltransferase: G1P + UTP → UDP-glucose

galactose1P uridyltransferase:

galactose1P + UDP-glucose → G1P + UDP-galactose

fates of galactose…

• UDP-galactose → UDP-glucose [epimerase]
• enter glycolysis (G1P → G6P → glycolysis)
• be converted to glucose (G1P → G6P → glucose)

Question 13

hereditary deficiencies in galactose metabolism

Answer 13

1. galactokinase def (nonclassical galactosemia)
2. galactose1P uridylyltransferase def (classical galactosemia) aka GALT

Question 14

galactokinase deficiency

Answer 14

galactose builds up

• in cells with aldose reductase activity (kidneys, retina, lens, nerve tissue, sem vesicles, ovaries): galactose → galactitol
  
  • galactitol buildup

genetics: rare, autosomal recessive

sx:

• elevation of galactose in blood and urine (galactosemia/uria)
• galactitol accumulation (if galactose in diet)
  
  • can cause cataracts

tx: dietary restriction

Question 15

GALT deficiency

galactose1P uridylyltransferase deficiency

Answer 15

classic galactosemia

GALT deficiency → accumulation of galactose1P and galactitol

genetics: autosomal recessive (1/30k)

symptoms: galactosemia, galatosuria, vomiting, diarrhea, jaundice

• accumulation of galactose1P and galactitol in nerve, lens, liver, kidney tissues → severe mental retardation, liver damage, cataracts

diagnosis/tx: prenatal chorionic villus sampling, newborn screening. removal of galactose from diet.

• still carries risk of devpt delays, premature ovarian failure for females

Question 16

overarching problem with accumulation of fructose1P and galactose1P

link to hyperuricemia

Answer 16

sequestration of inorganic phosphate!

due to…

deficiencies in aldolase B (F1P degradation) and GALT (galactose1P degradation)

leads ADP → AMP → IMP → uric acid buildup = hyperuricemia

can ALSO develop hyperuricemia via increased reabs via URAT1 (triggered by lactic acidosis, ketoacidosis)

Question 17

reducing sugars: definition, test

Answer 17

sugars with free aldehyde/ketone groups that can be oxidized to COOH

test: if they react with Cu (blue) → Cu2O (red/orange)

• shouldn’t see it in normal urine bc shouldnt see sugar in urine!

: urine dipstick to see if sugar is glucose (no glucose, but yet reducing sugar? not diabetes)