Week3biochem Flashcards
1
Q
vitamin precursor of active cofactors (i carbon transfer units)
A
folate
2
Q
where do we get folate from in our diet?
A
green leafy veggies, liver, legumes, yeast & fortified flour
3
Q
what part of the folate molecule is digested in the gut
A
glutamate tail–digested down to monoglutamate
4
Q
WHat happens to folate in the intestinal epithelial cells?
A
folate is reduced to N5-methyl THF
**becomes major form in the blood
5
Q
What happens to folate in the liver
A
poly-glutamated in the liver
**resets/starts pathway?
6
Q
spina bifida
A
- neural tube defects associated with folate deficiency before & during pregnancy
- *affected w/ SB cant make DNA
- **megaloblastic anemia: big RBCs but few
- ***DNA synthesis/division is delayed but cytoplasmic contents can still be made =BIG
- **found in bone marrow most often, blood occasional
7
Q
Hereditary folate malabsorption
A
inherited mutation in proton coupled folate transporter (PCFT: gene SCL46A1
**causes functional folate deficiency despite adequate folate in the diet
8
Q
causes of folate deficiency
A
- malabsorption
* not enough in diet
9
Q
What is the importance of dihydrofolate reductase (DHFR)
A
- enzyme that reduces folate –>dihydrofolate (FH2) –>tetrahydrofolate (FH4)
- *For metabolism of dietary folate & recycling oxidized folate to FH4
- **DHFR is a drug target: cancer, athritis, anitbacterial, & antimalarial
10
Q
What are the important Nitrogens in the tetrahydrofolate (THF or FH4)
A
N-5 & N-10
11
Q
ketogenic amino acids
A
AA can be degraded into Acetyl CoA and/or acetoacetate
12
Q
FH4 + formate gives us what product?
A
N10-formyl FH4
13
Q
N10-formyl FH4 can then make what compounds?
A
n10-formyl FH4 5,10methenyl THF 5,10methylene THF –> 5methyl THF —->methyl cobalmin
14
Q
Which step in the reduction of N10 formyl THF is not reversible? importance?
A
5,10 methylene THF –> 5 methyl THF is not reversible!
**called “methyl trap”
15
Q
THF + histidine –>?
A
FIGLU: 5-formimino THF
**can be made into 5,10 Methenyl THF
16
Q
When would you get a build up of FIGLU?
A
B12 deficiency
17
Q
which AA is the most important contributor to the 1-C pool?
A
serine!!
18
Q
THF + serine—> ?
A
5, 10 methylene THF
19
Q
contributors to the 1 C pool?
A
serine, glycine, choline, histidine, & formate
20
Q
Products of 1 carbon donations?
A
thymidine neucleotide, purine bases, methionine & s-adenosyl methinonine
21
Q
Important things about making thymidine nucleotide
A
- uses enzyme thymidylate synthase (TS)
- dUMP–>dTMP
- reduces methylene C to CH3 in process
- leaves cofactor in oxidized FH2 form to be reduced and accept 1 C grp from
- makes nucleotide for DNA
22
Q
what should a lady planning to b pregnant start taking? why?
A
- should take 400 ug/day of folate 1 month prior and up until 3 months after becoming pregnant
- prevents spina bifida
23
Q
Why does inhibitting DHFR or thymidylate synthase work as cancer drug/
A
- cancer cells divide rapidly & use lots of deoxynucleotides
- inhibition of these 2 enzymes prevents cell from getting nucleotides for DNA synthesis–>can’t grow or divide
- *harsh side effects because inhibits healthy cells as well as cancerous ones
24
Q
2 main cancer drugs
A
5-FU : 5- flourouracil
methotrexate
25
SAM: s-adenosyl methionine
provides methyl grps for biosynthetic reactions & can regenerate homocysteine
26
methyl trap hypothesis:
* N5methyl FH4 can only donate its 1 C to cobalamin --> methylcobalamin
* Methylcobalamin only donates methyl to homocysteine --> methionine
* *If B12 is missing, leaves folate trapped in N5methyl THF form & cant participate in other C transfers
* Sx's look like folate deficiency but are B12 deficiciency
27
Why does inhibitting DHFR or thymidylate synthase work as cancer drug/
* cancer cells divide rapidly & use lots of deoxynucleotides
* inhibition of these 2 enzymes prevents cell from getting nucleotides for DNA synthesis-->can't grow or divide
* *harsh side effects because inhibits healthy cells as well as cancerous ones
28
2 main cancer drugs
5-FU : 5- flourouracil
| methotrexate
29
SAM: s-adenosyl methionine
provides methyl grps for biosynthetic reactions & can regenerate homocysteine
30
methyl trap hypothesis:
* N5methyl FH4 can only donate its 1 C to cobalamin --> methylcobalamin
* Methylcobalamin only donates methyl to homocysteine --> methionine
* *If B12 is missing, leaves folate trapped in N5methyl THF form & cant participate in other C transfers
* Sx's look like folate deficiency but are B12 deficiciency
31
Cobalamin Rxn 2
homocysteine --> methionine
* methyl cobalamin consumed in rxn, but regenerated by methyl from N5methyl THF
* uses methionine synthase
32
pernicious anemia
megaloblastic anemia plus neuropathy
| **neurological symtpoms!!
33
movement of dietary b12
* 1st binds to R-binder protein in stomach
* R-binders digested, b12 binds to intrinsic factor protein
* complex is taken up by intestinal epi cells & transported into the blood w/ transcobalamin II
* most is stored in liver w/ cubillin
34
Cabalamin reaction 1
methylmalonyl CoA --> Succinyl COA--> TCA
* use B12 adenosyl cobalamin to methyl transfer (not swap)
* *adenosyl cobalamin not consumed in rxn
* use enzyme methylmalonyl CoA mutase
35
Cobalamin Rxn 2
homocysteine --> methionine
* methyl cobalamin consumed in rxn, but regenerated by methyl from N5methyl THF
* uses methionine synthase
36
hyperhomocysteinemia
* increase in homocysteine caused by:
1) mutation in methionine synthase
2) B12 deficiency
3) B6 deficiency
* associated with cardiovascular & neuro problems
37
what are glycogens main 2 functions?
1) intracellular glucose buffers
| 2) in hepatocytes, glycogen is the source of glucose for transport out into other cells
38
What are the most important cell types glycogen serves and why?
* skeletal & cardiac muscle: serves as a buffer for glucose 6-p for use in cell
* liver: serves as glucose buffer for blood
39
what are the 2 most common symptom presentations of glycogen metabolism deficiencies?
* fasting hypoglycemia
| * muscle pain during exercise
40
describe the structure of glucose
6 carbons with a hexagon ring of 5 carbons and an O
* side with O in ring is the reducing/1 end
* side with 2 OH is the non-reducing/4 end
41
@ types of C-C bonds in glycogen, what are they?
1: 4 forms linear chains
1: 6 make branch points
42
What is the purpose of forming UDP glucose before making glycogen?
1) UDP glucose serves as a handle to carry the glucose to elongating glycogen chain
2) the UDP bond to glucose holds energy to allow the addition of glucose to glycogen chains
43
what is the head protein that is necessary for glycogen synthesis?
glycogenin
44
What enzyme is used to link glucoses into glycogen chain & in what direction does this occur?
Glycogen synthase links glucose using 1:4 bond sites in the direction of the 4 carbon
(away from glycogenin which links at 1/reducing end of glucose)
45
When can branching occur & what enzyme performs this?
* occurs glycogen chain has reached 11 units long
* 4:6 transferase transfers a glucose chain from the end of linear chain (4 end) and makes a 1:6 bond to part of the linear chain closer to glycogenin than cleavage site
46
What is the purpose of branching and creating a "protein puffball"?
* increases solubility (many exposed OH groups)
| * can have many enzymes (100s) working on degradation or synthesis at 1 time [depending on the body's needs]
47
Steps in glycogenolysis (degradation)
1) glycogen phosphorylase cleaves units of glucose from glycogen chains & adds Pi to make glucose-1-phosphate (works until 4 units away from branch pt)
2) 4:4 transferase cleaves a 1,4 bond off branched chain & transfers 3 glucose units to end of another chain w/ 1:4 linkage
3) a-1,6 glucosidase activity hydrolyzes the remaining glucose's 1:6 bond to release single glucose
4) glycogen phosphorylase continues degrading chain until reaches another branch or the core
47
Steps in glycogenolysis (degradation)
1) glycogen phosphorylase cleaves units of glucose from glycogen chains & adds Pi to make glucose-1-phosphate (works until 4 units away from branch pt)
2) 4:4 transferase cleaves a 1,4 bond off branched chain & transfers 3 glucose units to end of another chain w/ 1:4 linkage
3) a-1,6 glucosidase activity hydrolyzes the remaining glucose's 1:6 bond to release single glucose
4) glycogen phosphorylase continues degrading chain until reaches another branch or the core
48
mutations in muscle glycogen phosphorylase causes:
```
GSD V (McArdles disease)
*presents with exercise intolerance
```
48
mutations in muscle glycogen phosphorylase causes:
```
GSD V (McArdles disease)
*presents with exercise intolerance
```
49
mutations in liver glycogen phosphorylase cause:
```
GSD VI (Hers disease)
*presents w/ fasting hypoglycemia
```
49
mutations in liver glycogen phosphorylase cause:
```
GSD VI (Hers disease)
*presents w/ fasting hypoglycemia
```
50
deficiency in a-1,6 glucosidase causes:
GSD III
*biggest concern with the=is deficiency is that glycogen gets too big & bursts the cell (since glycogen can only b built)
54
deficiency in a-1,6 glucosidase causes:
GSD III
*biggest concern with the=is deficiency is that glycogen gets too big & bursts the cell (since glycogen can only b built)
55
2 forms of glycogen phosphorylase & how to read their activity on a lineweaver-burke plot
a & b glycogen phosphorylase
| *a is higher activity because lower line on this plot= bigger vmax & lower Km
56
how is glycogen metabolism controlled?
by phosphorylation of glycogen phosphorylase & glycogen synthase
* fed= phosphorylase is inactive, gly. synthase is active, both unphosphorylated
* fasted= phosphorylase active, gly. synthase inactove, both phosphorylated
57
fasted state glycogen metabolism regulation in hepatocytes
epinephrine & glucagon cause cascade & turn off glycogen synthase, but turn on glycogen phosphorylase kinase--> glycogen phosphorylase-->glycogenolysis -->glucose
*glycogen0genesis is inhibitted
58
fed state glycogen metabolism regulation in hepatocytes
insulin turns on phosphatase cascade-->protein phosphorylase 1 is on & gly. symthase kinase 3 is off
* glycogen synthase is active & promotes glycogenogenesis
* gly. phosphorylase is inactive, inhibtting glycogenolysis
59
name the enzyme glucose 6-phosphorylase's importance during regulation of glycogen metabolism
critical for maintaining the buffer, by breaking down glucose-6-p in the liver into blood glucose (g6p cant cross membranes)
60
fasted state glycogen metabolism regulation in skeletal muscle
```
B epinephrine (no glucagon receptor) causes cascade to cAMP-->PKA which makes gly. synth inactive & gly. phosphorylase kinase active (latter ends up signaling for glucose production)
*protein phosphatase 1 is inactive while gly. synth kinase 3 is active
```
61
fed state glycogen metabolism regulation in skeletal muscle
insulin signals --> IRS1-->PI3K-->PDK-->PKB--> protein phosphatase 1 active & gly synth kinase3 inactive
* glycogen synthase is active (glycogenogenesis)
* gpk & gp are inactive so no genolysis
62
GSD 0
* glycogen synthase deficiency
* rare, autosomal recesssive
* norm glucose tolerance
* exercise intolerance
* cardiac & muscle hypertrophy
* may b cause of SIDS
63
GSD 1
aka von Giercke disease
*deficit in g6-phosphatase
*fasting hypoglycemia, lactic acidosis, hepatomegaly (gly accumulation)
*hyperuricemia & hyperlipidemia
*liver issue; not going to have exercise Sx's
Tx: avoid fasts & eat uncooked corn starch
64
GSD III
aka Cori disease
*deficit in 1,6-glucosidase activity of debranching enzyme
*fasting hypoglycemia, ketoacidosis, hyperlipidemia, hepatomagaly w/ hi AST/ALT
Tx: frequent hi carb meals
65
Difference between GSD IIIa & GSD IIIb?
GSD IIIa: affects liver & muscle
| GSD IIIb: affects only the liver & because of this is more preferable
66
GSD IV
* inability to make branches
* deficit of branching enzyme 4,6-transferase
* SX: FTT, hepatomegaly, liver failure, FATAL
67
GSD V
aka McArdle disease
* deficit in muscle glycogen phosphorylase
* late childhood onset of exercise intolerance, myoglobinuria after exercise
* increased creatine kinase, hi creatine kinase & ammonia after exercise
* Tx: avoid exercise, try to build tolerance
