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Enzymes and regulation

Revision as of 14:51, 5 January 2023 by Nikolas (talk | contribs) (Created page with "=== General rules about regulation: === * Hormones always regulate stuff indirectly * Hormones almost always regulate stuff covalently * Kinases or phosphatases almost always regulate stuff covalently * Something that’s not a protein can never regulate anything covalently directly The ones I think are most important are ''italicised''. Most of them are taken from Lehninger 6th edition. The “Page” column shows which page from the book has been used as a source....")
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General rules about regulation:

  • Hormones always regulate stuff indirectly
  • Hormones almost always regulate stuff covalently
  • Kinases or phosphatases almost always regulate stuff covalently
  • Something that’s not a protein can never regulate anything covalently directly

The ones I think are most important are italicised.

Most of them are taken from Lehninger 6th edition. The “Page” column shows which page from the book has been used as a source.

Acetyl-CoA carboxylase

Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme of fatty acid synthesis. It converts acetyl-CoA to malonyl-CoA with the help of the cofactors biotin, ATP and CO2. It is located in the cytosol.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Glucose Transcriptional Indirect ↑ Through PP2A and ChREBP 609
Xylulose 5-phosphate Transcriptional Indirect ↑ Through PP2A and ChREBP 609
PP2A Transcriptional and covalent Indirect and direct ↑ Through ChREBP and directly 609, 679
Insulin Covalent Indirect ↑ Through PP2A 679
Citrate Allosteric Direct ↑ 842
Cholesterol Transcriptional Indirect ↑ Through LXR 871
Glucagon, epinephrine Covalent Indirect ↓ Through PKA 679
AMP Covalent Indirect ↓ Through AMPK 679
Palmitoyl-CoA Allosteric Direct ↓ 842

Carbamoyl phosphate synthetase I

Carbamoyl phosphate synthetase I (CPS I) is the rate-limiting enzyme of urea synthesis. It should not be confused with carbamoyl phosphate synthetase II, which is the rate-limiting step of de novo pyrimidine synthesis. It is located in the mitochondria.

N-acetylglutamate is a breakdown product of amino acids. When more amino acids are broken down the urea cycle is sped up (by the increased amount of N-acetylglutamate) to prevent ammonia, another breakdown product of amino acids, from accumulating.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
N-acetylglutamate Allosteric Direct ↑ 708
Acetyl-CoA Allosteric Indirect ↑ Through N-acetylglutamate 708
Glutamate Allosteric Indirect ↑ Through N-acetylglutamate 708
Arginine Allosteric Indirect ↑ Through N-acetylglutamate 709

Carnitine acyl-transferase 1

Carnitine acyl-transferase 1 (CAT 1) is the main enzyme in the carnitine-dependent shuttle. Fatty acids are activated in the cytosol (on the outer mitochondrial membrane), but they must be transported into the mitochondrial matrix to be oxidized. Short and medium-length fatty acids can freely diffuse across the mitochondrial membrane, but long fatty acids (like palmitoyl-CoA) cannot. Palmitoyl-CoA is instead converted into palmitoylcarnitine by CAT1, which is shuttled across the mitochondrial membrane by a transport protein. When inside the mitochondrial matrix, palmitoylcarnitine is converted back into palmitoyl-CoA.

It is the rate-limiting step of beta oxidation. Malonyl-CoA is a product of fatty acid synthesis. Because malonyl-CoA inhibits CAT1, fatty acid synthesis inhibits beta oxidation.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Malonyl-CoA Allosteric Direct ↓ Malonyl-CoA is produced by ACC

Fructose 1,6-bisphosphatase (FBPase-1)

Fructose 1,6-bisphosphatase (FBPse-1) is the rate-limiting enzyme in gluconeogenesis. It is located in the cytosol.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Glucagon Allosteric Indirect ↑ Through F26BP 606
AMP Allosteric Direct ↓ 605
Insulin Allosteric Indirect ↓ Through F26BP 606
F26BP Allosteric Direct ↓ 605

Glucokinase (hexokinase IV)

Glucokinase is involved in glycolysis. It is located in the liver and beta-cells of the pancreas. Because glucokinase has a low affinity for glucose the liver will only store glucose as glycogen when the blood glucose level is high.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Insulin Transcription Indirect ↑ 952
Glucose Transport out of the nucleus Indirect ↑ Through a regulatory protein 603
Low [ATP] Transcription Indirect ↑ 603
Fructose 6-phosphate Transport into the nucleus Indirect ↓ Through a regulatory protein 603

Glycogen phosphorylase

Glycogen phosphorylase is the rate-limiting step of glycogenolysis. It requires PLP as a cofactor.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Glucagon Covalent Indirect ↑ In liver, through PKA 621
Epinephrine Covalent Indirect ↑ In muscle and liver, through PKA 621
[Ca2+] ↑ Covalent Indirect ↑ In muscle. Ca2+ is the signal for muscle contraction 621
[AMP] ↑ Allosteric Direct ↑ In muscle 621
Insulin Covalent Indirect ↓ 621
PP1 Covalent Direct and indirect ↓ Indirect via phosphorylase kinase. They often ask about this! 621
Glucose Allosteric Direct ↓ 622

Glycogen synthase

Glycogen synthase is the rate-limiting enzyme in glycogenesis (glycogen synthesis.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
G6P Covalent and allosteric Indirect (covalent) and direct (allosteric) ↑ Covalent: By making it easier for PP1 to dephosphorylate 623 (covalent), ass. prof. Lengyel (allosteric)
PP1 Covalent Direct ↑ 623
Insulin Covalent Indirect by two ways ↑ Through PP1 and GSK3 623
Glucose Covalent Indirect ↑ By making it easier for PP1 to dephosphorylate 623
Casein kinase II Covalent Direct ↓ 623
Glucagon, epinephrine Covalent Indirect ↓ Through PKA 623
GSK3 Covalent Direct ↓ 623
AMPK Covalent Direct ↓ Figure 23-40

Hexokinase I-III (not glucokinase)

Hexokinase is the rate-limiting step of glycolysis in all tissues except the liver and beta-cells. Because it has high affinity for glucose, all tissues that use hexokinase will utilize glucose even when the blood glucose level is normal.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Insulin Transcription Indirect ↑
Glucose Allosteric Direct ↑ 548, 591
Glucose 6-phosphate Allosteric Direct ↓ 602, 762

HMG-CoA reductase

HMG-CoA reductase (HMG-CoAR) is the rate-limiting enzyme of cholesterol synthesis. It is located in the membrane of ER.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Insulin Covalent Indirect ↑ Through PP2A 870
Low intracellular cholesterol Transcriptional Indirect ↑ Through SREBP and SCAP 871
Glucagon Covalent Indirect ↓ Through PKA 870
AMP Covalent Indirect ↓ Through AMPK 870
High intracellular cholesterol Proteolysis Indirect ↓ Through oxysterol with Insig 871

HMG-CoA synthase (mitochondrial)

Mitochondrial HMG-CoA synthase is the rate-limiting enzyme of ketone body synthesis. Cytosolic HMG-CoA synthase is an enzyme in the cholesterol synthesis, but it is not the rate-limiting one and is therefore not very important.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Acetyl-CoA Allosteric Direct ↑ Biochem 1 lecture
Succinyl-CoA Covalent Direct ↓ By succinylation Biochem 1 lecture

PEP carboxykinase

PEP carboxykinase is an irreversible enzyme in the gluconeogenesis. It is located in the cytosol.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Glucocorticoids (liver) Transcriptional ? ↑ Only in liver
Thiazolidinediones (in adipose tissue) Transcriptional ? ↑ Only in adipose tissue
Glucocorticoids (adipose tissue) Transcriptional ? ↓ Only in adipose tissue

Phosphofructokinase-1 (PFK1)

Phosphofructokinase-1 (PFK1) is the rate-limiting enzyme in glycolysis.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
F26BP Allosteric Direct ↑ 605
Insulin Allosteric and transcriptional Indirect ↑ Through F26BP
AMP, ADP Allosteric Direct ↑ 762
ATP Allosteric Direct ↓ 762
Glucagon, epinephrine Allosteric Indirect ↓ Through F26BP
Citrate Allosteric Direct ↓ 762

Pyruvate carboxylase

Pyruvate carboxylase is an irreversible enzyme in the gluconeogenesis. It is located in the mitochondria and requires biotin and ATP.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Acetyl-CoA Allosteric Direct ↑ 608

Pyruvate dehydrogenase complex

Pyruvate dehydrogenase complex (PDH) is an enzyme which connects the glycolysis to the TCA cycle by converting pyruvate to acetyl-CoA. It is located in the mitochondria. It requires 5 cofactors; TPP, lipoate, CoA, FAD and NAD.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
AMP Covalent Indirect ↑ Through pyruvate dehydrogenase kinase 654
CoA Allosteric Direct ↑ 654
NAD+ Allosteric Direct ↑ 654
Ca2+ Allosteric Direct ↑ 654
ATP Covalent Indirect ↓ Through pyruvate dehydrogenase kinase 654
Acetyl-CoA Allosteric Direct ↓ 654
NADH Allosteric Direct ↓ 654
Fatty acids Allosteric Direct ↓ 654

Pyruvate kinase

Pyruvate kinase is an irreversible enzyme in the glycolysis.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
F16BP Allosteric Direct ↑ 607
Insulin Covalent and transcriptional Indirect ↑ Covalent: Through PP1, only in liverTranscriptional: Through ChREBP 607
ADP Allosteric Direct ↑ 762
ATP Allosteric Direct ↓ 762
Long-chain fatty acid Allosteric Direct ↓ 607
Acetyl-CoA Allosteric Direct ↓ 607
Alanine Allosteric Direct ↓ 607
Glucagon Covalent Indirect ↓ Through PKA, only in liver 607