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Gastrointestinal System > HMP - Abali 3/8/16 > Flashcards

HMP - Abali 3/8/16 Flashcards

1
Q

HMP basics

A

hexose monophosphate pathway

aka…

  • pentose monophosphate pathway
  • phosphogluconate pathway
  • hexose monophosphate shunt
  • alt route for metabolism of glucose
    • produces NADPH and ribose (key for nt synthesis)
  • no ATP directly consumed or produced

involves mitochondria and pyruvate/malate shuttle

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2
Q

functions of HMP

A

1. generation of NADPH

  • req for reductive biochem rxns (FA synth, chol synth)

2. generation of ribose

  • req for nt and nucleic acid synth

3. in RBCs, serves a regenerative fx for glutathione

  • NADPH regenerates reduced form of glutathione (antioxidant, protects cells from ROS)
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3
Q

NADPH fx

diff b/w NADPH and NADH

A

reductive agent in many anabolic pathways

  • NADPH has a P group that NADH does not have
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4
Q

what processes/where is HMP involved?

A

HMP makes NADPH, which is key for many anabolic rxns

steroid synthesis

  • adrenal gland, testes, ovaries

FA synthesis

  • aidpose tissue, mammary gland, liver

cholesterol synthesis

  • liver

maintenance of reduced glutathione stock (antiox)

  • RBCs
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5
Q

stages of HMP

A

oxidative phase

  • produce NADPH

nonoxidative phase (reversible sugar interconversions)

  • ribulose-5-phosphate converted into…
    • ribose 5 P [nt synth]
    • glyceraldehyde 3 P [glycolysis int]
    • fructose 6 P [glycolysis int]
  • linked with needs of glycolysis, gluconeogenesis
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6
Q

how is the HMP linked with glycolysis

A

transketolase [needs thiamine pyrophosphate (TPP) prosthetic group] : catalyze transfers of 2C

transaldolase : catalyze transfers of 3C

*thiamine/B1 also critical for PDH complex, alpha ketoglutarate DH, branched chain alpha ketoacid DH)

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7
Q

flux/regulation of HMP

A

short term

  • glucose 6 phosphate dehydrogenase (G6PDH)
    • feedback inhibition via NADPH (competitive inhibitor)

long term

  • insulin → upreg transcription of G6PDH
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8
Q

TPP and Wernicke Korsakoff syndrome

A

transketolase requires TPP

if TPP binding is defective, can cause Wernicke Korsakoff syndrome and assoc neuropsych symptoms

  • paralysis of eye movements
  • abnormal gait
  • decreased mental fx
  • severely impaired memory
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9
Q

fates of HMP, determined by cellular need for:

NADPH only

A

FA synthesis, detox

  • ox rxns produce NADPH
  • non ox rxns convert ribulose-5-P → G6P to produce more NADPH
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10
Q

fates of HMP, determined by cellular need for:

NADPH

ribose 5 P

A

rapidly dividing cells

  • ox rxns produce NADPH + ribulose 5 P
    • isomerase converts ribulose-5-P → ribose 5 P
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11
Q

fates of HMP, determined by cellular need for:

NADPH

pyruvate

A

RBCs

  • ox rxns produce NADPH + ribulose 5 P
  • nonox rxns convert ribulose-5-P → fructose 6 P, glyceraldehyde 3 P
    • these ints are shuttled into glycolysis → pyruvate
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12
Q

pathways requiring NADPH

A
  1. reductive biosynthesis
  2. cytochrome P450 monooxygenase

3. phagocytosis by WBCs

  1. NO synthesis
  2. reduction of hydrogen peroxide (ROS)
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13
Q

NAPDH use in:

reductive biosynth

A

NAPDH is required in anabolic pathways that synthesize

  • FAs
  • cholesterol
  • steroids
  • [regenerate] reduced form of glutathione antioxidant
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14
Q

NAPDH use in:

cyt P450s

A

cyt P450s typically add an -OH to compounds to make them more soluble

mitochondrial system

  • steroid biosynth (adrenals, testes/ovaries, placenta)
  • bile acid, active vit D3 biosynth (liver)

microsomal system

  • detox (liver)
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15
Q

NAPDH use in:

phagocytosis in WBCs

A

pathogens are phagocytosed → brought into phagolysosome

respiratory burst: O2 → superoxide radical O2- [NAPDH oxidase]

  • O2- → H2O2 → HOCl (hypochlorous acid aka Clorox) [myeloperoxidase]
    • toxic to bacteria!
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16
Q

importance of H2O2 degradation

A
  • ROS can damage proteins, DNA, unsaturated lipids → lead to cell death
  • implicated in cancer, aging, inflammatory injury

glutathione peroxidase and catalase convert H2O2 → H2O

17
Q

NAPDH use in:

NO synthesis

A

L-Arg + O2 → L-citrulline + NO [NO synthase]

  • NADPH oxidized

***breakdown pathway (PDE5) is inhibited by Viagra!

NO fx

  • sm muscle relaxant
  • prevents platelet aggregation
  • neurotransmitter
  • mediates macrophage bactericidal/tumericidal activity
18
Q

glutathione peroxidase

A

tripeptide: Gly, Cys, Glu
* when oxidized via glutathione peroxidase, it dimerizes : no protective properties

in order to regain anti-ROS properties, it needs to be reduced

  • reduction occurs via glutathione reductase + NADPH
19
Q

importance of reduced glutathione (GSH) in RBCs

A

RBC is a highly oxidizing environment

every day, spontaneous conversion of Hb-Fe+2 → Hb-Fe+3 + superoxide (rate: 1%/hour)

  • only Fe+2 can bind oxygen! need to get the Fe+3 reduced → Fe+2
  • also, superoxide → H2O2 → membrane damage!

need GSH handy to break down the ROS before membrane integrity is compromised

  • NADPH and glutathione reductase are constantly required for this process
  • cell burns up to 10% of its ATP on the HMP pathway to make sure NADPH stocks are sufficient
20
Q

how/why does G6PDH deficiency affect RBCs?

A

G6P + NADP → 6 P gluconate + NADPH

RBCs with G6PDH deficiency can’t make the NADPH they need to keep GSH (reduced glutathione) levels up high enough to prevent membrane damage

→ hemolytic anemia (caused by intensification of oxidative environment in RBC: drugs, chemical in fava beans)

  • sign: Heinz bodies (GS-SG + MetHb)
21
Q

Heinz bodies

A

seens with G6PDH deficiency

ox damage to Hb → cross-linking and precipitation of Hb seen as small inclusions : Heinz bodies

22
Q

G6PDH deficiency

A

aka favism

  • most common genetic enzymopathy (400 variants)
  • X-linked recessive

homozygous recessive

  • high levels of hemolysis, anemia

heterozygous

  • typically asymptomatic unless exposed to compounds that increase oxidative stress/ROS
    • drugs (anti-malarial primaquine)
    • fava beans

**condition selected for by conferred relative resistance to infection by Plasmodium falciparum

23
Q

G6PDH deficiency

G6PDH A- vs. G6PDH Mediterranean

A

type I (most severe) → type IV (least severe)

type III G6PDH A- (African) : young cells can provide some level of enzyme activity

type II G6PDH Mediterranean : most cells provide negligible enzyme activity

A- starts at a higher enzyme activity, lasts longer than Mediterranean

24
Q

G6PDH A- vs. G6PDH Mediterranean

comparison of…

  • chronic hemolysis
  • degree of hemolysis
  • G6PDH defect
  • enzyme half life
  • hemolysis with drugs
  • hemolysis with infection
A

G6PDH A- /// G6PDH Mediterranean

chronic hemolysis : none /// none

degree of hemolysis : moderate /// severe

G6PDH defect : old RBC /// all RBC

enzyme half life : 14 days /// hrs [normal approx 60 days]

hemolysis with drugs : unusual /// common

hemolysis with infection : common /// common

25
Q

other sources of NADPH for tissues

A

(besides HMP)…

  • malic enzyme
  • nicotinamide nucleotide transhydrogenase

need mitochondria for both of these means of producing NADPH

Gastrointestinal System (35 decks)

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