Enzymes and regulation

Page created on May 14, 2018. Last updated on March 11, 2020 at 17:39

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 bolded.

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